Acute Lymphoblastic Leukemia Cases Research Articles

Tonsillectomy and hematologic malignancy: Should routine pediatric tonsillectomy specimens be sent to pathology?

ObjectivesRoutine pediatric tonsillectomy ± adenoidectomy (T ± A) is one of the most common procedures for children worldwide, accounting for approximately 2000 procedures per year at our institution. To determine the utility of pathologic analysis of routine, nonsuspicious pediatric tonsil specimens, we investigated the incidence of hematologic and lymphoid malignancy diagnosed at the time of or following T ± A. MethodsRetrospective review of patients 0–18 years undergoing T ± A between 2012 and 2020 with or without pathologic analysis. ResultsIncluded were 14,141 patients who underwent routine T ± A (mean age 11 ± 4.6 years, 48% female). Of these, tonsils of 2464 patients were sent to pathology, where zero were found to harbor malignancy. Seven patients (0.050%) developed malignancy after T ± A. Of these, 4 had unremarkable tonsils per pathology, and 3 did not have tonsils analyzed. There were 5 cases of Acute Lymphocytic Leukemia (ALL, 0.035%), 1 case of Acute Myeloid Leukemia (0.007%), and 1 case of Lymphoma (0.007%). The average length of time from T ± A to diagnosis was 2.4 ± 1.8 years. ConclusionNo cases of occult malignancy were identified in specimens from routine T ± A with pathologic analysis, even among patients who later developed malignancy. This study suggests that sending routine pediatric T ± A specimens for formal pathologic analysis is an inefficient use of resources without appreciably improving the quality and safety of patient care.

Pretransplant HLA mistyping in diagnostic sample of a T-ALL patient due to loss of heterozygosity in the major histocompatibility complex

PurposeThe degree of HLA compatibility between donor and recipient in hematopoietic stem cell transplantation is critical. In this report, we describe an acute lymphoblastic leukemia case with loss of heterozygosity (LOH) encompassing the entire HLA. MethodsHLA molecular typing was performed on peripheral blood (PB) and buccal swabs (BS). Chromosomal microarray analysis (CMA) was performed using a whole genome platform. ResultsTyping results on PB sample collected during blast crisis demonstrated homozygosity at the-B,-C,-DR, and -DP loci. A BS sample demonstrated heterozygosity at the above loci. A subsequent PB sample drawn after count recovery confirmed heterozygosity. The CMA performed on PB samples collected during blast crisis revealed a large terminal region of copy-neutral LOH involving chromosome region 6p25.3p21.31, spanning approximately 33.32 Mb. The results of the CMA assay on sample collected after count recovery did not demonstrate LOH. ConclusionsLOH at the HLA gene locus may significantly influence the donor search resulting in mistakenly choosing homozygous donors. We recommend confirming the HLA typing of recipients with hematological malignancies when homozygosity is detected at any locus by using BS samples, or alternatively from PB when remission is achieved.

T-Cell Acute Lymphoblastic Leukemia: Biomarkers and Their Clinical Usefulness.

T-cell acute lymphoblastic leukemias (T-ALL) are immature lymphoid tumors localizing in the bone marrow, mediastinum, central nervous system, and lymphoid organs. They account for 10–15% of pediatric and about 25% of adult acute lymphoblastic leukemia (ALL) cases. It is a widely heterogeneous disease that is caused by the co-occurrence of multiple genetic abnormalities, which are acquired over time, and once accumulated, lead to full-blown leukemia. Recurrently affected genes deregulate pivotal cell processes, such as cycling (CDKN1B, RB1, TP53), signaling transduction (RAS pathway, IL7R/JAK/STAT, PI3K/AKT), epigenetics (PRC2 members, PHF6), and protein translation (RPL10, CNOT3). A remarkable role is played by NOTCH1 and CDKN2A, as they are altered in more than half of the cases. The activation of the NOTCH1 signaling affects thymocyte specification and development, while CDKN2A haploinsufficiency/inactivation, promotes cell cycle progression. Among recurrently involved oncogenes, a major role is exerted by T-cell-specific transcription factors, whose deregulated expression interferes with normal thymocyte development and causes a stage-specific differentiation arrest. Hence, TAL and/or LMO deregulation is typical of T-ALL with a mature phenotype (sCD3 positive) that of TLX1, NKX2-1, or TLX3, of cortical T-ALL (CD1a positive); HOXA and MEF2C are instead over-expressed in subsets of Early T-cell Precursor (ETP; immature phenotype) and early T-ALL. Among immature T-ALL, genomic alterations, that cause BCL11B transcriptional deregulation, identify a specific genetic subgroup. Although comprehensive cytogenetic and molecular studies have shed light on the genetic background of T-ALL, biomarkers are not currently adopted in the diagnostic workup of T-ALL, and only a limited number of studies have assessed their clinical implications. In this review, we will focus on recurrent T-ALL abnormalities that define specific leukemogenic pathways and on oncogenes/oncosuppressors that can serve as diagnostic biomarkers. Moreover, we will discuss how the complex genomic profile of T-ALL can be used to address and test innovative/targeted therapeutic options.

Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires \u03b2-catenin activity to drive T-cell acute lymphoblastic leukemia

Spi-1 Proto-Oncogene (SPI1) fusion genes are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) cases but are insufficient to drive leukemogenesis. Here we show that SPI1 fusions in combination with activating NRAS mutations drive an immature T-ALL in vivo using a conditional bone marrow transplant mouse model. Addition of the oncogenic fusion to the NRAS mutation also results in a higher leukemic stem cell frequency. Mechanistically, genetic deletion of the β-catenin binding domain within Transcription factor 7 (TCF7)-SPI1 or use of a TCF/β-catenin interaction antagonist abolishes the oncogenic activity of the fusion. Targeting the TCF7-SPI1 fusion in vivo with a doxycycline-inducible knockdown results in increased differentiation. Moreover, both pharmacological and genetic inhibition lead to down-regulation of SPI1 targets. Together, our results reveal an example where TCF7-SPI1 leukemia is vulnerable to pharmacological targeting of the TCF/β-catenin interaction.

Efficacy of Therapeutic Leukapheresis in Acute Lymphoblastic Leukemia Presenting with Leukostasis

Therapeutic leukapheresis is performed in patients having hyperleukocytosis, leading to leukostasis. The aim of this study was to evaluate the efficacy of therapeutic leukapheresis in reducing white cell count in leukemic patients with symptoms of leukostasis. Two cases of acute lymphoblastic leukemia, admitted to the hematology intensive care unit between January and May 2015, were taken up for therapeutic leukapheresis, using COBE Spectra Cell Separator. The first patient was a 24-year-old male, admitted with fever, weakness, headache, blurred vision, and a total leukocyte count (TLC) of 564,000/μL. The second patient was a 36-year-old male admitted with fever, headache, dyspnea, and a TLC of 530,000/μL. The first patient had a 31.38% and 30.19% reduction in TLC after first and second procedures, respectively. The second patient had a reduction in TLC of 31.7% and 31.41% after first and second procedures, respectively. This significant decrease in white cell count achieved reversal of symptoms of leukostasis. Patients with hyperleukocytosis may present as a medical emergency, requiring prompt recognition and initiation of therapy to prevent respiratory failure or intracranial hemorrhage. Leukapheresis removes circulating blasts quickly to alleviate symptoms.

Clinical Observation on 98 Cases of Hematological Malignancies Treated with Autologous Hematopoietic Stem Cell Transplantation Cryopreserved By Ladder-Style Freezing from Low Temperature Refrigerator to Liquid Nitrogen

Background: Programmed cooling - 196℃ liquid nitrogen preservation and non- programmed cooling - 80℃ low temperature refrigerator preservation have been widely used in Auto- HSCT. Programmed cooling and - 196℃ liquid nitrogen preservation can set the rate of temperature fall in advance and standardize the cooling process, reducing the damage to hematopoietic stem cells caused by temperature fall. But programmed cooling is a time-consuming process and it needs to purchase expensive control rate freezer. Non- programmed cooling - 80℃ low temperature refrigerator preservation is easy to operate, but it cannot keep a long preservation period. Since 2002, we tried combining two preservation methods into one: first we placed freezer bags in - 80℃ low temperature refrigerator and then placed them in -196℃ liquid nitrogen tank for long-term preservation, with the purpose of prolonging the cryopreservation of stem cells.Method:We observed the influence of cryopreservation of hematopoietic stem cells with ladder-style freezing from low temperature refrigerator to liquid nitrogen in transplantation treatment of hematological malignancies, and analyzed the survival condition of patients after hematopoietic stem cell transplantation.We retrospectively analyzed the clinical datas of 98 patients with hematological malignancies treated by hematopoietic stem cell transplantation from 2002-01 to 2016-12 in our center.Results: 98 patients, 56 males and 42 females, aged 14-69 years (avenge age36.46±14.19 years). Disease subtypes: 10 cases of acute lymphoblastic leukemia(ALL), 24 cases of acute non- lymphoblastic leukemia(ANLL) , 11 cases of multiple myeloma(MM), 53 cases of malignant lymphoma(ML). One case failed in implantation due to intracranial hemorrhage and the other 97 cases all succeeded in hematopoietic reconstitution. The median survival time was 47 months and the average follow-up time was 50.11 months. The average time needed to neutrophil count ≥0.5×109/L was 9.24±1.89d, and the average time needed to platelet count≥20×109/L without platelet transfusion for 3 days was 11.04±1.84d. The median survival time was 47.6 months (1~80 months). The overall survival rates of 1 year, 3-year and 5-year were (97.2±1.9) %, (84.2±4.6) % and (77.8±5.6) %, respectively. PFS (progression-free survival) of patients in 3 years and 5 years were (74.4±5.1)% and (61.2±6.2)% (Figure1), which is consistent with data reported by other transplantation centers. In this study, it is found that the application of auto-HSCT has significantly improved OS and PFS of patients with acute leukemia, malignant lymphoma and multiple myeloma, but there is no significant difference in OS and PFS among three groups(Figure2)(P=0.537). The survival condition of CR1 patients was better than no-CR1 patients(Figure3). The complication about transplantation mainly were digestive tract symptoms. 9.18% patients complicated with liver function injury and 58.16% patients got infection.We continuously improved cryophylactic agent and obtained cryoprotectant formed by 3%hydroxyethyl starch, 4% albumin and 5% DMSO to replace the traditional 10% DMSO cryoprotectant used in programmed cooling. During stem cell infusion, the occurrence rate of complication was 8.16%, significant lower than the occurrence rate of adverse events occurring in the usage of 10% DMSO cryoprotectant.Conclusions: ladder-style freezing from low temperature refrigerator to liquid nitrogen with cryoprotectant that is formed by 3% hydroxyethyl starch, 4% albumin and 5% dimethyl sulfoxide (DMSO) for cryopreservation of hematopoietic stem cells. It can reach the same clinical transplantation effect with traditional programmed cooling freezing method in autologous hematopoietic stem cells transplantation (auto-HSCT) and can effectively improve OS, PFS of hematological malignancies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Inotuzumab Ozogamicin for Relapsed/Refractory Acute Lymphoblastic Leukemia in the Global Phase 3 INO-VATE Trial: Efficacy and Safety By Baseline CD22 Expression Level

Abstract Introduction: CD22 is expressed in >90% of cases of B-cell acute lymphoblastic leukemia (ALL) making it an attractive target for the treatment of B-cell malignancies. Inotuzumab ozogamicin (InO), an anti-CD22 antibody conjugated to calicheamicin, has demonstrated significantly greater efficacy vs standard care (SC) therapies in patients with relapsed/refractory (R/R) ALL in the INO-VATE trial (Kantarjian et al, 2016). Herein, the efficacy and safety of InO vs SC in patients with baseline leukemic blast CD22 positivity ≥90% vs Methods: In this phase 3 trial (NCT01564784) completed on LSLV 04Jan2017, patients with R/R ALL (including ~15% in each arm with Philadelphia-positive ALL) due to receive salvage 1 or 2 therapy were randomized to InO (1.8 mg/m2/cycle [0.8 mg/m2 on day 1; 0.5 mg/m2 on days 8 and 15 of a 21-28 day cycle for ≤6 cycles]) or SC (investigator choice of fludarabine/cytarabine [Ara-C]/granulocyte colony-stimulating factor [FLAG], Ara-C + mitoxantrone, or high-dose Ara-C). Efficacy was assessed in the intent-to-treat (ITT) population; safety was assessed in all patients who received ≥1 dose of study drug. Central flow cytometry was used to assess minimal residual disease (MRD) negativity ( Results: 326 patients (InO, n=164; SC, n=162) were included in the ITT analysis population with both arms being well balanced for baseline characteristics. Most patients in both arms had high (≥90%) CD22 positivity at baseline (InO, 65%; SC, 57%), with only a small fraction exhibiting CD22 positivity Conclusion: At least 90% of blasts were CD22-positive in the majority of patients. The greatest benefit from treatment with InO was observed in those patients with CD22 positivity ≥90%, while statistical differences in PFS, DOR, and OS could not be shown in patients with CD22 positivity Download : Download high-res image (147KB) Download : Download full-size image Disclosures Kantarjian: Bristol-Meyers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Delta-Fly Pharma: Research Funding; Pfizer: Research Funding. Stock: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy. DeAngelo: Glycomimetics: Research Funding; Amgen: Consultancy, Research Funding; Immunogen: Honoraria, Research Funding; Incyte: Consultancy, Honoraria; Blueprint Medicines: Honoraria, Research Funding; Takeda Pharmaceuticals U.S.A., Inc.: Honoraria; Shire: Honoraria; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding; ARIAD: Consultancy, Research Funding; BMS: Consultancy; Celgene: Research Funding. Jabbour: Bristol-Myers Squibb: Consultancy. O'Brien: Gilead Sciences, Inc.: Consultancy, Other: Research Support: Honorarium, Research Funding; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Other: Research Support: Honorarium, Research Funding; Pfizer: Consultancy, Research Funding; ProNAI: Other: Research Support: Honorarium, Research Funding; Astellas: Consultancy; TG Therapeutics: Consultancy, Other: Research Support: Honorarium, Research Funding; GSK: Consultancy; Celgene: Consultancy; Acerta: Other: Research Support: Honorarium, Research Funding; Regeneron: Other: Research Support: Honorarium, Research Funding; AbbVie: Consultancy; Amgen: Consultancy; Sunesis: Consultancy; Aptose Biosciences, Inc.: Consultancy; Janssen: Consultancy; Vaniam Group LLC: Consultancy; Alexion: Consultancy. Wang: Pfizer: Employment, Equity Ownership. Paccagnella: Pfizer: Employment. Nguyen: Navigate BioPharma Services, INC: Employment. Sleight: Pfizer: Employment, Equity Ownership. Vandendries: Pfizer: Employment, Equity Ownership. Laird: Pfizer: Employment. Advani: Takeda/ Millenium: Research Funding; Pfizer: Consultancy.

Mechanically Disaggregated Unfixed Trephine Biopsies Can be Used for Diagnostic Immunophenotyping in Acute Leukaemia

An adequate bone marrow sample is essential for a rapid diagnosis of acute leukaemia by multicolour flow cytometry enabling the assignment of lineage and choice of therapy.Diagnosis is sometimes delayed due to difficulties in of obtaining a bone marrow aspirate due to a ‘dry tap’.In this study we evaluated immunophenotyping of mechanically disaggregated unfixed bone marrow trephine biopsies from 62 paediatric and adult patients at diagnosis (mostly acute leukemia). We compared the results to immunophenotyping of blood and aspirate samples and the trephine biopsy histology.In 26 of 62 cases no disease was present in the blood and the aspirate was a ‘dry tap’. In 24 of 26 cases a diagnosis was reached by immunophenotyping from the disaggregated bone marrow biopsy. Results were concordant with histopathology in all 24 cases (22 acute lymphoblastic leukemia(ALL) cases, 2 acute myeloid leukemia (AML) cases). In 2 cases insufficient cells were obtained from the disaggregated biopsy to reach a diagnosis.In 36 of 62 cases immunophenotyping was performed on disaggregated unfixed bone marrow trephine biopsies and compared to immunophenotyping on blood and/or aspirate as well as histology. The immunophenotyping findings were concordant in 33 cases between the (21 ALL, 6 AML, 3 myelodysplastic syndromes|(MDS), 3 other haematological malignancies). In 3 cases insufficient cells could be obtained from the disaggregated biopsy. In one of these the histology from the bone marrow biopsy showed cortical bone only, while the other two showed AML and MDS.In conclusion these data confirm earlier reports that immunophenotyping of mechanically disaggregated unfixed trephines is a useful diagnostic adjunct particularly where a dry tap has occurred. DisclosuresNo relevant conflicts of interest to declare.

A case of Philadelphia chromosome‐positive acute lymphocytic leukaemia with type I CD36 deficiency

CD36 is a glycoprotein expressed on platelets and monocytes of the blood. There are two types of CD36 deficiency, type I and type II. Individuals with type I-deficiency do not express CD36 in any cell type and can produce the CD36 antibody, which causes pathological conditions, such as fetal/neonatal alloimmune thrombocytopenia (FNAIT) and platelet transfusion refractory (PTR), through antigenic exposure via transfusion or pregnancy. We experienced a case of Philadelphia-positive acute lymphoblastic leukaemia with PTR. In addition to the CD36 antibody, multiple-specificity HLA antibodies were present in the patient's plasma, requiring transfusion of HLA-compatible and CD36-negative platelets (PC-HLA). Since the number of donors was limited, it was necessary to set-up a blood transfusion schedule so that hyper-fractionated cyclophosphamide, vincristine and doxorubicin therapy (hyper-CVAD) and ponatinib combination chemotherapy could be safely administered to achieve molecular remission. Rituximab administration resulted in reduced levels of both CD36 antibody and HLA antibody. Given the expression of CD36 on haematopoietic stem cells and the limited availability of CD36-negative PC-HLA, haematopoietic stem cell transplantation (HSCT) was not considered to be an option. If CD36-negative, allogeneic haematopoietic stem cell donors are unable to be found, the indications for HSCT in patients with type I CD36-deficiency should be carefully weighed. In the present case, molecular remission has been able to be maintained to the present day after completion of a two-year maintenance regimen.

Analysis of the clinical characteristics of 24 cases of hematological malignancies with SET-NUP214 fusion gene

目的探讨SET-NUP214融合基因在血液恶性肿瘤中的表达，分析其相关的临床及生物学特征。方法回顾性分析2012年1月至2018年12月北京大学人民医院诊断的24例SET-NUP214融合基因阳性血液恶性肿瘤患者的临床资料，并采用Kaplan-Meier法进行生存分析。结果24例患者中，急性淋巴细胞白血病（ALL）15例（T-ALL 13例，B-ALL 2例）、急性髓系白血病（AML）7例，T/髓混合急性白血病2例。13例T-ALL患者免疫表型以CD3+CD2−为主要特征，73.3％的ALL患者伴有髓系标志表达，85.7％的AML患者表达CD7。24例患者诱导化疗完全缓解（CR）率91.7％。全部患者均接受异基因造血干细胞移植，中位随访24个月，AML和ALL的3年无复发生存（RFS）率分别为85.7％和33.3％，差异无统计学意义（P＝0.128）。比较13例SET-NUP214阳性与62例SET-NUP214阴性T-ALL患者的疗效，诱导化疗CR率分别为92.3％和93.5％（P＝0.445），诱导化疗4周CR率分别为69.2％和72.6％（P＝0.187），差异均无统计学意义。接受造血干细胞移植后，SET-NUP214阳性T-ALL患者的3年RFS率（38.5％）明显低于SET-NUP214阴性T-ALL患者（66.4％）（P＝0.028）。结论SET-NUP214融合基因主要见于T细胞源性血液肿瘤，伴SET-NUP214融合基因T-ALL预后较差。

Inhibition of DNA damage response pathway using combination of DDR pathway inhibitors and radiation in treatment of acute lymphoblastic leukemia cells.

An alarming increase in acute lymphoblastic leukemia cases among children and adults has attracted the attention of researchers to discover new therapeutic strategies with a better prognosis. In cancer cells, theDNA damage response (DDR) pathway elements have been recognized to protect tumor cells from various stresses and cause tumor progression;targeting these DDR members is an attractive strategy for treatment of cancers. The inhibition of theDDR pathway in cancer cells for the treatment of cancers has recently been introduced. Hence, effective treatment strategies are needed for this purpose. Chemotherapy in combination with radiotherapy is considered a potential therapeutic strategy for acute leukemia. This review aims to assess the synergistic effects of these inhibitors with irradiation for the treatment of leukemia.

Constitutive JAK/STAT signaling is the primary mechanism of resistance to JAKi in TYK2-rearranged acute lymphoblastic leukemia.

Activating TYK2-rearrangements have recently been identified and implicated in the leukemogenesis of high-risk acute lymphoblastic leukemia (HR-ALL) cases. Pre-clinical studies indicated the JAK/TYK2 inhibitor (JAKi), cerdulatinib, as a promising therapeutic against TYK2-rearranged ALL, attenuating the constitutive JAK/STAT signaling resulting from the TYK2 fusion protein. However, following a period of clinical efficacy, JAKi resistance often occurs resulting in relapse. In this study, we modeled potential mechanisms of JAKi resistance in TYK2-rearranged ALL cells in vitro in order to recapitulate possible clinical scenarios and provide a rationale for alternative therapies. Cerdulatinib resistant B-cells, driven by the MYB-TYK2 fusion oncogene, were generated by long-term exposure to the drug. Sustained treatment of MYB-TYK2-rearranged ALL cells with cerdulatinib led to enhanced and persistent JAK/STAT signaling, co-occurring with JAK1 overexpression. Hyperactivation of JAK/STAT signaling and JAK1 overexpression was reversible as cerdulatinib withdrawal resulted in re-sensitization to the drug. Importantly, histone deacetylase inhibitor (HDACi) therapies were efficacious against cerdulatinib-resistant cells demonstrating a potential alternative therapy for use in TYK2-rearranged B-ALL patients who have lost response to JAKi treatment regimens.

Effects of Chemotherapy Agents on Circulating Leukocyte Populations: Potential Implications for the Success of CAR-T Cell Therapies.

Simple SummaryCAR-T cell therapy is a new approach to cancer treatment that is based on manipulating a patient’s own T cells such that they become able to seek and destroy cancer cells in a highly specific manner. This approach is showing remarkable efficacy in treating some types of blood cancers but so far has been much less effective against solid cancers. Here, we review the diverse effects of chemotherapy agents on circulating leukocyte populations and find that, despite some negative effects over the short term, chemotherapy can favourably modulate the immune systems of cancer patients over the longer term. Since blood is the starting material for CAR-T cell production, we propose that these effects could significantly influence the success of manufacturing, and anti-cancer activity, of CAR-T cells. Thus, if timed correctly, chemotherapy-induced changes to circulating immune cells could allow CAR-T cells to unleash more effective anti-tumour responses.Adoptive T-cell therapy using autologous T cells genetically modified to express cancer-specific chimeric antigen receptors (CAR) has emerged as a novel approach for cancer treatment. CAR-T cell therapy has been approved in several major jurisdictions for treating refractory or relapsed cases of B-cell precursor acute lymphoblastic leukaemia and diffuse large B-cell lymphoma. However, in solid cancer patients, several clinical studies of CAR-T cell therapy have demonstrated minimal therapeutic effects, thus encouraging interest in better integrating CAR-T cells with other treatments such as conventional cytotoxic chemotherapy. Increasing evidence shows that not only do chemotherapy drugs have tumoricidal effects, but also significantly modulate the immune system. Here, we discuss immunomodulatory effects of chemotherapy drugs on circulating leukocyte populations, including their ability to enhance cytotoxic effects and preserve the frequency of CD8+ T cells and to deplete immunosuppressive populations including regulatory T cells and myeloid-derived suppressor cells. By modulating the abundance and phenotype of leukocytes in the blood (the ‘raw material’ for CAR-T cell manufacturing), we propose that prior chemotherapy could facilitate production of the most effective CAR-T cell products. Further research is required to directly test this concept and identify strategies for the optimal integration of CAR-T cell therapies with cytotoxic chemotherapy for solid cancers.

The New Therapeutic Strategies in Pediatric T-Cell Acute Lymphoblastic Leukemia.

Childhood acute lymphoblastic leukemia is a genetically heterogeneous cancer that accounts for 10–15% of T-cell acute lymphoblastic leukemia (T-ALL) cases. The T-ALL event-free survival rate (EFS) is 85%. The evaluation of structural and numerical chromosomal changes is important for a comprehensive biological characterization of T-ALL, but there are currently no genetic prognostic markers. Despite chemotherapy regimens, steroids, and allogeneic transplantation, relapse is the main problem in children with T-ALL. Due to the development of high-throughput molecular methods, the ability to define subgroups of T-ALL has significantly improved in the last few years. The profiling of the gene expression of T-ALL has led to the identification of T-ALL subgroups, and it is important in determining prognostic factors and choosing an appropriate treatment. Novel therapies targeting molecular aberrations offer promise in achieving better first remission with the hope of preventing relapse. The employment of precisely targeted therapeutic approaches is expected to improve the cure of the disease and quality of life of patients. These include therapies that inhibit Notch1 activation (bortezomib), JAK inhibitors in ETP-ALL (ruxolitinib), BCL inhibitors (venetoclax), and anti-CD38 therapy (daratumumab). Chimeric antigen receptor T-cell therapy (CAR-T) is under investigation, but it requires further development and trials. Nelarabine-based regimens remain the standard for treating the relapse of T-ALL.

The Prenatal Origin of Childhood Leukemia: Potential Applications for Epidemiology and Newborn Screening.

Childhood leukemias are heterogeneous diseases with widely differing incident rates worldwide. As circulating tumors, childhood acute leukemias are uniquely accessible, and their natural history has been described in greater detail than for solid tumors. For several decades, it has been apparent that most cases of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) initiate in utero. Circumstantial evidence in support of this contention includes the young age of onset and high rate of concordance among identical twins. “Backtracking” of leukemic somatic mutations, particularly gene translocations, to cord blood and dried blood spots collected during the perinatal period has provided molecular proof of prenatal leukemogenesis. Detection of a patient's leukemia translocation in easily accessible birth samples, such as dried blood spots, is straightforward with the knowledge of their idiosyncratic breakpoints. However, to translate these findings into population-based screening and leukemia prevention requires novel methods able to detect translocations at all possible breakpoints when present in a low frequency of cells. Several studies have attempted to screen for leukemic translocations, mainly the common ETV6-RUNX1 translocation, in cord blood samples from healthy children. Most studies have reported finding translocations in healthy children, but estimates of prevalence have varied widely and greatly exceed the incidence of leukemia, leading to concerns that technical artifact or contamination produced an artificially inflated estimate of translocation prevalence at birth. New generation techniques that capture the presence of these translocations at birth have the potential to vastly increase our understanding of the epidemiology of acute leukemias. For instance, if leukemic translocations are present at birth in a far higher proportion of children than eventually develop acute leukemia, what are the exposures and somatic molecular events that lead to disease? And could children with translocations present at birth be targeted for prevention of disease? These questions must be answered before large-scale newborn screening for leukemia can occur as a public health initiative. Here, we review the literature regarding backtracking of acute leukemias and the prevalence of leukemic translocations at birth. We further suggest an agenda for epidemiologic research using new tools for population screening of leukemic translocations.

The Domino Effect-Treatment of Superior Vena Cava Obstruction Triggering Tumor Lysis Syndrome: A Case Report

Oncological emergencies present in a multitude of manners-structural, metabolic, hematologic, etc. affecting multiple systems, often. Urgent institution of therapy is often required for a successful outcome. Occasionally, the treatment of one emergency can initiate a related or unrelated emergency, necessitating management of all the complications simultaneously. Superior vena cava obstruction (SVCO) is a medical emergency and most often manifests in patients with a malignant disease process requiring immediate diagnostic evaluation and therapy due to its’ life threatening presentation. The management of the SVCO is usually with chemotherapy, radiotherapy or intervention. In cases of large tumor burden, management of SVCO can trigger other complications. Tumor lysis syndrome is an oncologic emergency, which is characterized by a massive release of intracellular potassium, phosphate, and nucleic acid metabolites into the systemic circulation, which can be life-threatening. We present the case of a T-cell acute lymphoblastic leukemia with superior vena cava syndrome, developing tumor lysis syndrome on instituting definitive chemotherapy in a young patient. Doi: 10.28991/SciMedJ-2021-0301-6 Full Text: PDF

Chloroma: an uncommon presentation of the acute lymphopblastic leukaemia (ALL) in a child

Leukemia is the most common malignancy of childhood. Chloromas are a rare presentation of an underlying leukemia. Here, we discuss a rare case of acute lymphoblastic leukemia (ALL) presenting with swelling over right eye. The patient was evaluated radiologically for the extension of disease and treatment planning. ALL was diagnosed with complete blood count and bone marrow examination. The orbital swelling was the initial presentation which led to further diagnosis of acute lymphoblastic leukemia (ALL) in our case. Chloroma is usually a common clinical presentation of acute myeloid leukemia (AML), however, it may rarely be found in a case of acute lymphoblastic leukemia (ALL) such as ours.

Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1-driven acute lymphoblastic leukemia.

The cellular receptor Notch1 is a central regulator of T-cell development, and as a consequence, Notch1 pathway appears upregulated in >65% of the cases of T-cell acute lymphoblastic leukemia (T-ALL). However, strategies targeting Notch1 signaling render only modest results in the clinic due to treatment resistance and severe side effects. While many investigations reported the different aspects of tumor cell growth and leukemia progression controlled by Notch1, less is known regarding the modifications of cellular metabolism induced by Notch1 upregulation in T-ALL. Previously, glutaminolysis inhibition has been proposed to synergize with anti-Notch therapies in T-ALL models. In this work, we report that Notch1 upregulation in T-ALL induced a change in the metabolism of the important amino acid glutamine, preventing glutamine synthesis through the downregulation of glutamine synthetase (GS). Downregulation of GS was responsible for glutamine addiction in Notch1-driven T-ALL both invitro and invivo. Our results also confirmed an increase in glutaminolysis mediated by Notch1. Increased glutaminolysis resulted in the activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, a central controller of cell growth. However, glutaminolysis did not play any role in Notch1-induced glutamine addiction. Finally, the combined treatment targeting mTORC1 and limiting glutamine availability had a synergistic effect to induce apoptosis and to prevent Notch1-driven leukemia progression. Our results placed glutamine limitation and mTORC1 inhibition as a potential therapy against Notch1-driven leukemia.

T-ALL can evolve to oncogene independence.

The majority of cases of T-cell acute lymphoblastic leukemia (T-ALL) contain chromosomal abnormalities that drive overexpression of oncogenic transcription factors. However, whether these initiating oncogenes are required for leukemia maintenance is poorly understood. To address this, we developed a tetracycline-regulated mouse model of T-ALL driven by the oncogenic transcription factor Lmo2. This revealed that whilst thymus-resident pre-Leukemic Stem Cells (pre-LSCs) required continuous Lmo2 expression, the majority of leukemias relapsed despite Lmo2 withdrawal. Relapse was associated with a mature phenotype and frequent mutation or loss of tumor suppressor genes including Ikzf1 (Ikaros), with targeted deletion Ikzf1 being sufficient to transform Lmo2-dependent leukemias to Lmo2-independence. Moreover, we found that the related transcription factor TAL1 was dispensable in several human T-ALL cell lines that contain SIL-TAL1 chromosomal deletions driving its overexpression, indicating that evolution to oncogene independence can also occur in human T-ALL. Together these results indicate an evolution of oncogene addiction in murine and human T-ALL and show that loss of Ikaros is a mechanism that can promote self-renewal of T-ALL lymphoblasts in the absence of an initiating oncogenic transcription factor.

Down syndrome and acute lymphoblastic leukemia

In an analysis of 653 cases of acute lymphoblastic leukemia associated with Down syndrome (DS-ALL) collected from clinical research groups worldwide, the 8-year disease-free survival for DS-ALL was 64%, which was worse than the 81% for non-DS-ALL during the same period. This could be because DS-ALL has less hyperdiploidy and ETV6-RUNX1 abnormalities, which have a favorable prognosis, more Ph-like ALL, which has a poor prognosis, as well as more adverse deaths due to infectious complications. It has been reported that optimizing the treatment intensity using minimal residual disease and by strengthening the measures against adverse effects improve the treatment outcome of DS-ALL. The incidence of DS-ALL is reported to be 20 times higher than that of non-DS-ALL. The mechanism is believed to be through proliferation of the lymphoid system caused by HMGN1 on chromosome 21 as well as activation of JAK-STAT and proliferation of ALL cells caused by overexpression of CRLF2, such as P2RY8-CRLF2 fusion. The CRLF2 abnormality is found in 30-60% of DS-ALL cases. In the future, treatment of CRLF2, targeting JAKs downstream of CRLF2, and administration of blinatumomab or CAR-T therapy will be incorporated into DS-ALL treatment.