The outcome of relapsed childhood acute lymphoblastic leukemia after allogeneic hematopoietic stem-cell transplantations: A single-center experience.

In children with high-risk childhood acute leukemia who undergo allogeneic hematopoietic stem-cell transplantation (allo-HSCT), relapse is still the leading cause of treatment failure. The prognosis is poor, yet prospective studies have only limited data on risk factors and outcomes. We aimed to understand the outcomes and prognostic factors for patients with acute lymphoblastic leukemia (ALL) who relapsed following allo-HSCT. We analyzed retrospectively 46 children with childhood acute lymphoblastic leukemia who had relapsed after receiving their first alloHSCT. All these patients received salvage chemotherapy which consisted of fludarabine, cytarabine, and idarubicin before performing a second alloHSCT. The median follow-up of the 46 patients after the first transplantation was 366 days. The median time from first allo-HSCT to relapse was 278.4 ± 238.4 days. Forty-six patients received salvage chemotherapy before the second alloHSCT, and CR was achieved in 32 of 46 patients. However, only 17 (37%) of 46 patients received a second allo-HSCT, and 15 of 46 patients died from disease progression, infections, and bleeding. Twelve patients are still alive after the second allo-HSCT. Two-year overall survival (OS) was 38.9%. Local therapy was given to 10 (21.8%) patients, either as part of systemic therapy or alone. In multivariate analyses, the time of relapse and curative salvage therapy with a second allo-HSCT were identified as significant prognostic factors for OS. Children with leukemia who had relapsed after the first allo-HSCT received salvage chemotherapy. Our statistical analysis showed that the second HSCT could be beneficial for outcomes if patients relapsed beyond 180 days of the first allo-HSCT.

[The value of minimal residual disease and IKZF1 deletion for predicting prognosis in adult patients with B-cell acute lymphoblastic leukemia].

Objective: To reassess the prognostic value of minimal residual disease (MRD) and IKZF1 gene deletions in adults with B-cell acute lymphoblastic leukemia (B-ALL) who received pediatric-specific chemotherapy regimens during the Nanfang Hospital PDT-ALL-2016 trial. Methods: We retrospectively analyzed the prognosis of 149 adult patients with B-ALL who were admitted to Nanfang Hospital from January 2016 to September 2020. Prognostic factors were identified using Cox regression models. Results: The complete remission rate was 93.2% in 149 patients, with a 5-year overall survival (OS) rate of (54.3±5.0) % and a cumulative incidence of relapse (CIR) of (47.5±5.2) %. The Cox regression analysis revealed that MRD positivity at day 45 (MRD(3)) after induction therapy was independently associated with relapse risk (HR=2.535, 95%CI 1.122-5.728, P=0.025). Deletion of IKZF1 gene was independently associated with mortality risk (HR=1.869, 95%CI 1.034-3.379, P=0.039). Based on MRD(3) and IKZF1 gene status, we categorized adult patients with B-ALL into the low-risk (MRD(3)-negative and IKZF1 gene deletion-negative) and high-risk (MRD(3)-positive and/or IKZF1 gene wild type) groups. The 5-year OS and CIR rates were (45.5±6.0) % vs (69.4±8.6) % (P<0.001) and (61.6±8.3) % vs (25.5±6.5) % (P<0.001), respectively, in the high-risk and low-risk groups, respectively. The multivariate analysis showed that the high-risk group was an independent risk factor for OS (HR=3.937, 95%CI 1.975-7.850, P<0.001) and CIR (HR=4.037, 95%CI 2.095-7.778, P<0.001) . Conclusion: The combined use of MRD and IKZF1 gene in prognostic stratification can improve clinical outcome prediction in adult patients with B-ALL, helping to guide their treatment.

Foetal haemoglobin elevation, unfavourable prognosis, and protective role of genetic variants HBG2 rs7482144, HBS1L-MYB rs9399137 and BCL11A rs4671393 in children with ALL.

In acute lymphoblastic leukaemia (ALL), elevated foetal haemoglobin (HbF) levels have been associated with the prognosis of patients. Genetic variants in HbF regulatory genes: BAF chromatin remodelling complex subunit (BCL11A), HBS1L-MYB transcriptional GTPase intergenic region (HBS1L-MYB), Krüppel-like factor 1 (KLF1), haemoglobin gamma subunit 2 (HBG2), haemoglobin gamma subunit 1 (HBG1), and haemoglobin subunit beta pseudogene 1 (HBBP1) are often associatedwith elevatedHbF concentration. This study investigated the association of genetic variants in HbF regulatory genes with HbF concentration, unfavourable prognosis, and outcome in children with ALL.We quantified HbF concentration and genotyped 17 genetic variants in 48 patients with ALL and 64 children without ALL as a reference group. HbF concentrationwas higher in patients than in the reference group (4.4%vs 1.4%), and 75%(n = 36) of thepatientshadHbF>2.5%.Unfavourable prognosis ALL was established in 68.8% (n = 33) of the patients. Variant HBG2 rs7482144 was associated with high HbF concentration (P = 0.015); while HBS1L-MYB rs9399137 (P = 0.001), HBG2 rs7482144 (P = 0.001) and the ß-globin genes HBG2, HBG1, and HBPP1 haplotypeTGC(P = 0.017) with unfavourable prognosisALL.Additionally, variantBCL11A rs4671393 showed a protective role (P = 0.0001). In conclusion, variants HBG2 rs7482144, HBS1L-MYB rs9399137 and BCL11A rs4671393 may play a significant role in ALL.

Triple Trouble.

We present a case of a 24-year-old female recently diagnosed with acute leukemia who came with complaints of fever for 14 days, progressive lower limb weakness, and multiple episodes of vomiting in the last 1 day. In nerve conduction studies, a diagnosis of Guillain-Barré syndrome (GBS) was established. Fever with thrombocytopenia workup revealed a positive dengue nonstructural protein 1 (NS1) and immunoglobulin M (IgM) report. Immunophenotyping confirmed pre-B acute lymphoblastic leukemia (ALL). As leukemia is an immunocompromised state, the peripheral nervous system vulnerability is increased, or infection could precipitate an immune neuropathy. About 10% of adult ALL presents with central nervous system (CNS) leukemias; a higher incidence is seen in mature B ALL. There is some evidence to suggest immunosuppression secondary to intensive chemotherapy (vincristine-induced dying back neuropathy), which was not started in our case. This rare combination in a short period of time with a worsening situation paralyzed the line of management. Few reports described GBS in patients with dengue in adults. The association of Guillan-Barre syndrome and ALL could be coincidental or has a pathophysiological basis and is under basic investigation.

Frequency and Aberrant CD Marker Profile of Acute Leukaemias.

OBJECTIVE: To determine the frequency of different types of acute leukaemia and their subtypes along with associated aberrant CD markers. STUDY DESIGN: Descriptive study. Place and Duration of the Study: Department of Immunology Armed Forces Institute of Pathology, National University of Medical Sciences, Rawalpindi, Pakistan, from November 2021 to October 2023. METHODOLOGY: All samples received for flow cytometric immunophenotyping with suspicion of acute leukaemia were included in the study. Cells were stained with fluorochrome labelled monoclonal antibodies against lineage-specific cluster of differentiation (CD) markers through a lyse-wash procedure. Acquisition and analysis were done using multi-parameter BD FACS Canto II Flow cytometer and BD FACS Diva software, respectively. Data were entered and analysed using SPSS v 23.0. RESULTS: Over a period of 2 years, a total of 1,115 suspected patients were tested for acute leukaemia. Among them, 728 (65.3%) were males and 387 (34.7%) were females, with mean age 28 ± 21 years, ranging from 1 week to 87 years. Among a total of 875/1115 (78.5%) diagnosed cases of acute leukaemia, AML was the most common leukaemia present in 408/875 (46.6%) patients followed by B-ALL and T-ALL in 384/875 (43.8%) and 70/87 (8%) patients, respectively (p = 0.5712). Aberrant CD markers were detected in 109/875 (12.5%) leukaemias (p = 0.0628). The most common aberrant CD markers in B-ALL were CD13 and CD33 present in 30/384 (7.8%) cases separately. Among AML and T-ALL most common aberrant CD markers were CD7 and CD33 present in 25/408 (6.13%) and 7/70 (10%) cases, respectively. CONCLUSION: Special consideration should be given to the presence of aberrant CD markers when assigning lineages to acute leukaemias. They may be important diagnostic, prognostic, and management tools for institution of immunotherapy. KEY WORDS: Aberrant CD markers, Acute leukaemia, CD Markers, Flow cytometry, Immunophenotyping.

[Efficacy of allogeneic hematopoietic stem cell transplantation based on a total body irradiation conditioning treatment regimen for adult acute lymphocytic leukemia].

Objective: To analyze the efficacy of allo-HSCT with total body irradiation (TBI) and chemotherapy alone in the treatment of adult ALL and to explore the factors affecting prognosis. Methods: The clinical data of 95 adult patients with ALL who underwent allo-HSCT from January 2015 to August 2022 were included. According to the conditioning regimen, the patients were divided into two groups: the TBI plus cyclophosphamide (TBI/Cy) group (n=53) and the busulfan plus cyclophosphamide (Bu/Cy) group (n=42). Hematopoietic reconstitution after transplantation, GVHD, transplantation-related complications, relapse rate (RR), non-relapse mortality (NRM), OS, and LFS were compared, and the factors related to prognosis were analyzed. Results: The median time of neutrophil engraftment was 14 (10-25) days in the TBI/Cy group and 14 (10-24) days in the Bu/Cy group (P=0.106). The median time of megakaryocyte engraftment was 17 (10-42) days in the TBI/Cy group and 19 (11-42) days in the Bu/Cy group (P=0.488). The incidence of grade Ⅱ-Ⅳ acute GVHD (aGVHD) in the TBI/Cy and Bu/Cy groups was 41.5% and 35.7%, respectively (P=0.565). The incidence of grade Ⅲ-Ⅳ aGVHD in these two groups was 24.5% and 4.8%, respectively (P=0.009). The incidence of severe chronic GVHD in the two groups was 16.7% and 13.5%, respectively (P=0.689). The incidence of cytomegalovirus infection, Epstein-Barr virus infection, severe infection, and hemorrhagic cystitis in the two groups was 41.5% and 35.7% (P=0.565), 34.0% and 35.7% (P=0.859), 43.4% and 33.3% (P=0.318), and 20.8% and 50.0% (P=0.003), respectively. The median follow-up time was 37.1 months and 53.3 months in the TBI/Cy and Bu/Cy groups, respectively. The 2-year cumulative RR was 17.0% in the TBI/Cy group and 42.9% in the Bu/Cy group (P=0.017). The 2-year cumulative NRM was 24.5% and 7.1%, respectively (P=0.120). The 2-year LFS was 58.5% and 50.0%, respectively (P=0.466). The 2-year OS rate was 69.8% and 64.3%, respectively (P=0.697). In the multivariate analysis, the conditioning regimen containing TBI was a protective factor for relapse after transplantation (HR=0.304, 95% CI 0.135-0.688, P=0.004), whereas the effect on NRM was not significant (HR=1.393, 95% CI 0.355-5.462, P=0.634). Infection was an independent risk factor for OS after allo-HSCT in adult patients with ALL. Conclusion: allo-HSCT based on TBI conditioning regimen had lower relapse rate and lower incidence of hemorrhagic cystitis for adult ALL, compared with chemotherapy regimen. While the incidence o grade Ⅲ/Ⅳ aGVHD was hgher in TBI conditioning regimen than that in chemotherapy regimen.

"Myeloid" Mutations in ALL Are Not Uncommon: Implications for Etiology and Therapies.

SUMMARY: In Blood Cancer Discovery, Saygin and colleagues report that somatic variants that are recurrent in myeloid malignancies can also occur with high frequency (16%) in adult acute lymphoblastic leukemia (ALL) where they correlate with older age, diagnosis following genotoxic therapy for a prior malignancy and worse outcome to chemotherapy. Mutations in these "myeloid" genes can precede ALL diagnosis and arise in hematopoietic stem or progenitor cells that clonally expand and differentiate into both lymphoblasts and nonmalignant myeloid cells, supporting a role for clonal hematopoiesis as premalignant state outside the context of myeloid malignancies and providing implications for both ALL etiology and therapeutic intervention. See related article by Saygin et al., p. 164 (4).

Causal inference for time-to-event data with a cured subpopulation.

When studying the treatment effect on time-to-event outcomes, it is common that some individuals never experience failure events, which suggests that they have been cured. However, the cure status may not be observed due to censoring which makes it challenging to define treatment effects. Current methods mainly focus on estimating model parameters in various cure models, ultimately leading to a lack of causal interpretations. To address this issue, we propose 2 causal estimands, the timewise risk difference and mean survival time difference, in the always-uncured based on principal stratification as a complement to the treatment effect on cure rates. These estimands allow us to study the treatment effects on failure times in the always-uncured subpopulation. We show the identifiability using a substitutional variable for the potential cure status under ignorable treatment assignment mechanism, these 2 estimands are identifiable. We also provide estimation methods using mixture cure models. We applied our approach to an observational study that compared the leukemia-free survival rates of different transplantation types to cure acute lymphoblastic leukemia. Our proposed approach yielded insightful results that can be used to inform future treatment decisions.

A Rare Case of Congenital Nephrogenic Diabetes Insipidus Associated with Aquaporin 2 Gene Mutation and Subsequent Acute Lymphoblastic Leukemia: Impact of Steroids on Kidney Function.

BACKGROUND Nephrogenic diabetes insipidus (NDI) is a rare renal disorder that can be congenital, and is caused by mutations in either aquaporin 2 or arginine vasopressin receptor 2, or it can be secondary to kidney disease or electrolyte imbalance. The clinical signs of NDI include polyuria, compensatory polydipsia, hypernatremic dehydration, and growth retardation without prompt treatment. In this report, we present the case of a patient with congenital NDI who was later diagnosed with acute lymphoblastic leukemia (ALL). With dexamethasone treatment, he had uncontrolled polyuria and polydipsia. Our aim was to concentrate on the impact of steroids on the kidneys. CASE REPORT Our patient presented at the age of 9 months with signs of severe dehydration that were associated with polyuria. His laboratory examinations revealed hypernatremia and decreased urine osmolality. He was diagnosed with NDI and his exome sequence revealed a homozygous mutation at the nucleotide position AQP2 NM_000486.6: c.374C>T (p.Thr125Met). He was treated with hydrochlorothiazide and amiloride. Then, at age 19 months, he presented with gastroenteritis and a complete blood count (CBC) showed high white blood cell count and blast cells. He was diagnosed with (ALL) and began receiving chemotherapy, during which again developed polydipsia and polyuria, which could not be controlled with an increased dosage of hydrochlorothiazide. CONCLUSIONS We report a rare case of NDI caused by a missense mutation in the aquaporin 2 gene. One year later, the child developed ALL, and treatment with dexamethasone led to an uncompensated state of polydipsia and polyuria.

Inotuzumab ozogamicin for the treatment of adult acute lymphoblastic leukemia: past progress, current research and future directions.

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.

Impact of Fee For Service on the Efficiency and Survival of Seguro Popular's Patients With Acute Lymphoblastic Leukemia in Mexico.

PURPOSE: Cost containment and efficiency in the provision of health care are primary concerns for health systems that aim to provide affordable, high-quality care. Between 2005 and 2015, Seguro Poplar's Fund against Catastrophic Expenditures (FPGC) funded ALL treatment in Mexico. Before January 1, 2011, FPGC reimbursed a fixed amount per patient according to risk. In 2011, the per capita reimbursement method changed to fee for service. We used this natural experiment to estimate the impact of the reimbursement policy change on average expenditure and quality of care for ALL treatment in Mexico. METHODS: We used nationwide reimbursement data from the Seguro Poplar's FPGC from 2005 to 2015. We created a patient cohort to assess 3-year survival and estimate the average reimbursement before and after the fee-for-service policy. We examined survival and expenditure impacts, controlling for patients' and providers' characteristics, including sex, risk (standard and high), the volume of patients served, type of institution (federally funded v other), and level of care. To quantify the impact, we used a regression discontinuity approach. RESULTS: The average reimbursement for standard-risk patients in the 3-year survival cohort was $16,512 US dollars (USD; 95% CI, 16,042 to 17,032) before 2011 and $10,205 USD (95% CI, 4,659 to 12,541) under the fee-for-service reimbursement scheme after 2011. The average annual reimbursement per patient decreased by 136% among high-risk patients. The reduction was also significant for the standard-risk cohort, although the magnitude was substantially smaller (34%). CONCLUSION: As Mexico's government is currently restructuring the health system, our study provides evidence of the efficiency and effectiveness of the funding mechanism in the Mexican context. It also serves as a proof of concept for using administrative data to evaluate economic performance and quality of care of publicly funded health programs.

Investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment.

Defining genetic factors impacting chemotherapy failure can help to better predict response and identify drug resistance mechanisms. However, there is limited understanding of the contribution of inherited noncoding genetic variation on inter-individual differences in chemotherapy response in childhood acute lymphoblastic leukemia (ALL). Here we map inherited noncoding variants associated with treatment outcome and/or chemotherapeutic drug resistance to ALL cis-regulatory elements and investigate their gene regulatory potential and target gene connectivity using massively parallel reporter assays and three-dimensional chromatin looping assays, respectively. We identify 54 variants with transcriptional effects and high-confidence gene connectivity. Additionally, functional interrogation of the top variant, rs1247117, reveals changes in chromatin accessibility, PU.1 binding affinity and gene expression, and deletion of the genomic interval containing rs1247117 sensitizes cells to vincristine. Together, these data demonstrate that noncoding regulatory variants associated with diverse pharmacological traits harbor significant effects on allele-specific transcriptional activity and impact sensitivity to antileukemic agents.

Periorbital cellulitis as the initial presentation of acute lymphoblastic leukaemia.

A girl in early childhood with no significant medical history developed left eye periorbital oedema and erythema. She was treated with intravenous antibiotics for suspected severe periorbital cellulitis. Despite treatment, the patient's cellulitis progressed into necrotising fasciitis, and she was transferred for ophthalmology review and imaging. A CT scan and eye swab culture-confirmed Staphylococcus aureus periorbital cellulitis. Incidentally, pathology revealed significant pancytopenia suspicious of leukaemia. The patient underwent bone marrow biopsy and was diagnosed with B-cell acute lymphoblastic leukaemia (ALL). A multidisciplinary specialist assessment revealed no ocular evidence of leukaemia and no intraocular concerns. In medical literature, it is consistently found that cases of ALL initially manifesting as proptosis or eyelid oedema are invariably due to neoplastic infiltration. This case represents unique documentation where periorbital cellulitis is the initial presentation of B-cell ALL, underscoring the necessity to consider periorbital cellulitis as a possible differential diagnosis in ophthalmic manifestations of ALL.

Neuropsychological task outcomes among survivors of childhood acute lymphoblastic leukemia in Malaysia.

This study intended to explore the neuropsychological ramifications in childhood acute lymphoblastic leukemia (ALL) survivors in Malaysia and to examine treatment-related sequelae. A case-control study was conducted over a 2-year period. Seventy-one survivors of childhood ALL who had completed treatment for a minimum of 1 year and were in remission, and 71 healthy volunteers were enlisted. To assess alertness (processing speed) and essential executive functioning skills such as working memory capacity, inhibition, cognitive flexibility, and sustained attention, seven measures from the Amsterdam Neuropsychological Tasks (ANT) program were chosen. Main outcome measures were speed, stability and accuracy of responses. Mean age at diagnosis was 4.50 years (SD ± 2.40) while mean age at study entry was 12.18 years (SD ± 3.14). Survivors of childhood ALL underperformed on 6 out of 7 ANT tasks, indicating poorer sustained attention, working memory capacity, executive visuomotor control, and cognitive flexibility. Duration of treatment, age at diagnosis, gender, and cumulative doses of chemotherapy were not found to correlate with any of the neuropsychological outcome measures. Childhood ALL survivors in our center demonstrated significantly poorer neuropsychological status compared to healthy controls.

Infant Acute Lymphoblastic Leukemia-New Therapeutic Opportunities.

Infant acute lymphoblastic leukemia (Infant ALL) is a kind of pediatric ALL, diagnosed in children under 1 year of age and accounts for less than 5% of pediatric ALL. In the infant ALL group, two subtypes can be distinguished: KMT2A-rearranged ALL, known as a more difficult to cure form and KMT2A- non-rearranged ALL with better survival outcomes. As infants with ALL have lesser treatment outcomes compared to older children, it is pivotal to provide novel treatment approaches. Progress in the development of molecularly targeted therapies and immunotherapy presents exciting opportunities for potential improvement. This comprehensive review synthesizes the current literature on the epidemiology, clinical presentation, molecular genetics, and therapeutic approaches specific to ALL in the infant population.

Terminal deoxynucleotidyl transferase expression in different subtypes of childhood B-cell acute lymphoblastic leukemia.

The lack of expression of terminal deoxynucleotidyl transferase (TdT) is frequently associated with KMT2A-rearranged subtype of pediatric acute lymphoblastic leukemia (ALL). However, this association has not been investigated extensively in the Asian population. A retrospective analysis of TdT expression in pediatric B-cell ALL (B-ALL) was performed in patients treated using the Taiwan Pediatric Oncology Group (TPOG) ALL 2002 and 2013 protocols. Among the 331 patients with B-ALL, 12 patients showed TdT negativity at initial diagnosis. Among these, eight patients showed KMT2A rearrangement (66.7%). Other patients showing negative TdT expression had ETV6::RUNX1, MEF2D-rearranged, and other B-ALL subtypes. However, in the context of KMT2A-rearranged B-ALL (n = 20), only eight patients showed TdT negativity. The 5-year event-free survival and overall survival of patients with and without TdT expression were 83.8% versus 46.8% (P <0.001) and 86.3% versus 55.4% (P = 0.004), respectively. Moreover, several aberrant markers, such as CD2, CD56, CD7, and CD117, were rarely expressed in the B-ALL samples, and if expressed, they were enriched in specific genetic subtypes. The results of this study indicate that immunophenotypic features are correlated with specific genetic subtypes of childhood B-ALL.

EP300-ZNF384 transactivates IL3RA to promote the progression of B-cell acute lymphoblastic leukemia.

The EP300-ZNF384 fusion gene is an oncogenic driver in B-cell acute lymphoblastic leukemia (B-ALL). In the present study, we demonstrated that EP300-ZNF384 substantially induces the transcription of IL3RA and the expression of IL3Rα (CD123) on B-ALL cell membranes. Interleukin 3 (IL-3) supplementation promotes the proliferation of EP300-ZNF348-positive B-ALL cells by activating STAT5. Conditional knockdown of IL3RA in EP300-ZF384-positive cells inhibited the proliferation in vitro, and induced a significant increase in overall survival of mice, which is attributed to impaired propagation ability of leukemia cells. Mechanistically, the EP300-ZNF384 fusion protein transactivates the promoter activity of IL3RA by binding to an A-rich sequence localized at -222/-234 of IL3RA. Furthermore, forced EP300-ZNF384 expression induces the expression of IL3Rα on cell membranes and the secretion of IL-3 in CD19-positive B precursor cells derived from healthy individuals. Doxorubicin displayed a selective killing of EP300-ZNF384-positive B-ALL cells in vitro and in vivo. Collectively, we identify IL3RA as a direct downstream target of EP300-ZNF384, suggesting CD123 is a potent biomarker for EP300-ZNF384-driven B-ALL. Targeting CD123 may be a novel therapeutic approach to EP300-ZNF384-positive patients, alternative or, more likely, complementary to standard chemotherapy regimen in clinical setting.

Epidemiological characteristics and influencing factors of acute leukemia in children and adolescents and adults: a large population-based study.

OBJECTIVE: To assess the epidemiological characteristics and prognostic factors of acute leukemia (AL) in children and adolescents, and make comparisons between pediatric and adult patients. METHODS: This retrospective cohort study enrolled AL patients from the Surveillance, Epidemiology, and End Results (SEER) 1975-2016. OS in children and adolescents and adults with AL was compared and analyzed separately by age and AL subtype. RESULTS: Totally 61,694 AL patients were identified, with 45,411 (73.6%) adults and 16,283 (26.4%) children and adolescents. From 2000 to 2016, the incidence rates of AL [annual percent changes (APC) = 1.2, 95%CI = 0.9-1.6, P < 0.05] and acute lymphoblastic leukemia (ALL) (APC = 1.5, 95%CI = 1.1-1.8, P < 0.05) in children and adolescents were significantly increasing. For adults, AL (APC = 0.9, 95%CI = 0.3-1.5, P < 0.05), ALL (APC = 2.5, 95%CI = 2.0-3.1, P < 0.05) and acute myeloid leukemia (AML) (APC = 0.9, 95%CI = 0.4-1.5, P < 0.05) had significantly elevated incidence rates. Overall survival (OS) in children and adolescents with AL was significantly higher than that in adults with AL (log-rank P < 0.0001). OS in children and adolescents and adults with ALL, AML and AUL decreased with age (all log-rank P < 0.0001). Older age, male sex and black race were risk factors for the survival of children and adolescents and adults with ALL, AML and AUL. CONCLUSION: From 2000 to 2016, the incidence rates of AL in children and adolescents and adults were increasing. Children and adolescents with AL had significantly better OS than adults with AL, and OS declined with age in both children and adolescents and adults with ALL, AML and AUL.

A review of immunotargeted therapy for Philadelphia chromosome positive acute lymphoblastic leukaemia: making progress in chemotherapy-free regimens.

Philadelphia chromosome-positive acute lymphoblastic leukemia (PH + ALL) is the most common cytogenetic abnormality of B-ALL in adults and is associated with poor prognosis. Previously, the only curative treatment option in PH + ALL was allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Since 2000, targeted therapy combined with chemotherapy, represented by the tyrosine kinase inhibitor Imatinib, has become the first-line treatment for PH + ALL. Currently, the remission rate and survival rate of Imatinib are superior to those of simple chemotherapy, and it can also improve the efficacy of transplantation. More recently, some innovative immune-targeted therapy greatly improved the prognosis of PH + ALL, such as Blinatumomab and Inotuzumab Ozogamicin. For patients with ABL1 mutations and those who have relapsed or are refractory to other treatments, targeted oral small molecule drugs, monoclonal antibodies, Bispecific T cell Engagers (BiTE), and chimeric antigen receptor (CAR) T cells immunotherapy are emerging as potential treatment options. These new therapeutic interventions are changing the treatment landscape for PH + ALL. In summary, this review discusses the current advancements in targeted therapeutic agents shift in the treatment strategy of PH + ALL towards using more tolerable chemotherapy-free induction and consolidation regimens confers better disease outcomes and might obviate the need for HSCT.