Myeloid Leukemia In Children Research Articles

DOSE INTENSITY OF INDUCTION CHEMOTHERAPY IN PEDIATRIC ACUTE MYELOID LEUKEMIA: A SYSTEMATIC REVIEW AND META-ANALYSIS

Objective This study compares the dose intensity of induction regimens by evaluating outcomes such as early deaths, death in the first remission, and survival. The results of this study will contribute to the development of therapeutic protocols with a reasonable balance in the intensity of induction, allowing remission to be achieved with less toxicity, adapting and establishing the treatment for acute childhood myeloid leukemia in developing countries. Methods Pubmed and Scopus were used for systematic searches performed in January 2021. Descriptors involving specific or synonymic words such as Acute myeloid leukemia, pediatric, induction, and dose-intensity combined with Boolean operators AND and OR were used, without limits of time-frame or language. All relevant studies were read in full, and the data extraction was performed for those that fulfilled the inclusion criteria (patients aged between 0–21 years old, diagnosed with AML, describing results of induction regimens where one of the groups – intervention or comparison –included different dosing for the same chemotherapy drug). Were excluded the studies publishing exclusively Down's Syndrome patients and acute promyelocytic leukemia diagnosis, single-arm studies (with no comparator group), and studies where the intervention group had a different chemotherapy regimen than the comparator group. Results The initial search retrieved 1185 papers. In the second round of screening of the remaining 207 articles, full-text papers were assessed for eligibility. From the nine papers included with dose modification during the induction phase of chemotherapy treatment, six referred to changes on cytarabine (ARA-C), two on idarubicin (IDR), and two on daunorubicin (DNR) (one of these studies simultaneously changed ARA-C and DNR). Results showed no significant difference between standard vs. high doses for CR and death during induction. Relapse rates were higher in the standard-dose than in the high-dose arms (1.44; 95% IC: 1.22–1.69). Despite the higher risk of relapse in the standard-dose group, event-free survival analysis shows no significant difference between the arms of each study. Discussion The outcome of AML treatment in children and adolescents has improved over the last decades. Overall survival rates are now superior to 70% due to implementing strategies such as intensification of therapy, refinements in supportive care, and more precise risk classification. However, treatment-related deaths are exceptionally high in places with limited resources. Even regimens with standard-dose chemotherapy are associated with life-threatening complications due to profound myelosuppression and organ dysfunction. Establishing the best combination and sequence of treatment components, including hematopoietic stem cell transplantation, remains an unmet need. Conclusion There is no significant difference between standard vs. high doses of chemotherapy during induction for selected outcomes such as complete remission and event-free survival. Reducing the dose intensity of standard AML remission induction regimens should be investigated in regions with limited resources.

Chronic myeloid leukemia in childhood: a case report

Chronic myeloid leukemia is a rare hematological malignancy in the pediatric age group. It is a clonal hematopoietic stem cell disorder in which granulocytes are the major proliferative components with the presence of the BCR-ABL1 fusion gene. Here, we report a case of CML in a three - year child with a clinical presentation of fever and abdominal distension. The diagnosis was made based on bone marrow aspiration findings and molecular study.

Chronic Myeloid Leukemia in Children and Adolescents (A bout 2 cases)

Pediatric chronic myelogenous leukemia is a rare entity (2 to 5% of childhood leukemia) classified as myeloproliferative neoplasia characterized by the presence of the BCR-ABL fusion gene, the oncogenic product of the translocation (9; 22), responsible for the disease by its deregulated tyrosine kinase activity. Pediatric chronic myelogenous leukemia evolves spontaneously in three phases: chronic, accelerated and blast, during which the malignant clone gradually loses its capacity for differentiation. The diagnosis is based on the clinic mainly by the presence of a marked splenomegaly, the blood count by a hyperleukocytosis generally greater than 250,000 / mm³, myelogram which shows granular hyperplasia associated with no blast infiltration and morphologically define the stage of the disease, cytogenetics and molecular biology which confirms the diagnosis by the detection of the Philadelphia chromosome and more specifically the molecular abnormality BCR-ABL1. Imatinib is the treatment of choice for curative purposes used in our hospital structure, but regular monitoring of residual molecular disease and the absence of cytogenetic evolution are essential to understand resistance to TKIs (the inhibitor of tyrosine activity kinase) and detect disease progression. We report two observations of pediatric chronic myeloid leukemia, describing the different diagnostic aspects and which were in agreement with clinical and biological data in the literature.

Chronic Myeloid Leukemia in Children: Immune Function and Vaccinations.

Children with CML need TKI treatment for many years, and the lack of knowledge about immune dysfunction with TKI has hindered routine immunizations. This review attempts to provide an overview of the effects of TKIs licensed for children (e.g., imatinib, dasatinib, and nilotinib) on immune function, as well as its implications on immunizations. We discuss surveillance strategies (e.g., immunoglobulin blood serum levels and hepatitis B reactivation) and immunizations. All inactivated vaccines (e.g., influenza, pneumococcal, and streptococcal) can be given during the treatment of CML in the chronic phase, although their efficacy may be lower. As shown in single cases of children and adults with CML, live vaccines (e.g., varicella, measles, mumps, rubella, and yellow fever) may be administered under defined circumstances with great precautions. We also highlight important aspects of COVID-19 in this patient population (e.g., the outcome of COVID-19 infection in adults with CML and in children with varying hemato-oncological diseases) and discuss the highly dynamic field of presently available different vaccination options. In conclusion, TKI treatment for CML causes humoral and cellular immune dysfunction, which is mild in most patients, and thus infectious complications are rare. Routine immunizations are important for health maintenance of children, but vaccinations for children with CML on TKI therapy should be carefully considered.

Obstructive Jaundice due to Pancreatic Head Mass: A Rare and Unusual Presentation of Acute Myeloid Leukemia in Children.

Obstructive Jaundice due to Pancreatic Head Mass: A Rare and Unusual Presentation of Acute Myeloid Leukemia in Children.

What Is Abnormal in Normal Karyotype Acute Myeloid Leukemia in Children? Analysis of the Mutational Landscape and Prognosis of the TARGET-AML Cohort.

Normal karyotype acute myeloid leukemia (NK-AML) constitutes 20–25% of pediatric AML and detailed molecular analysis is essential to unravel the genetic background of this group. Using publicly available sequencing data from the TARGET-AML initiative, we investigated the mutational landscape of NK-AML in comparison with abnormal karyotype AML (AK-AML). In 164 (97.6%) of 168 independent NK-AML samples, at least one somatic protein-coding mutation was identified using whole-genome or targeted capture sequencing. We identified a unique mutational landscape of NK-AML characterized by a higher prevalence of mutated CEBPA, FLT3, GATA2, NPM1, PTPN11, TET2, and WT1 and a lower prevalence of mutated KIT, KRAS, and NRAS compared with AK-AML. Mutated CEBPA often co-occurred with mutated GATA2, whereas mutated FLT3 co-occurred with mutated WT1 and NPM1. In multivariate regression analysis, we identified younger age, WBC count ≥50 × 109/L, FLT3-internal tandem duplications, and mutated WT1 as independent predictors of adverse prognosis and mutated NPM1 and GATA2 as independent predictors of favorable prognosis in NK-AML. In conclusion, NK-AML in children is characterized by a unique mutational landscape which impacts the disease outcome.

Tyrosine Kinase Inhibitors and Beyond for Chronic Myeloid Leukemia in Children.

Chronic myeloid leukemia (CML) is rare in children but presents a unique challenge as recent drug innovations have turned CML into a chronic disease with implications for treatment into adulthood. With the approval of newer-generation tyrosine kinase inhibitors (TKIs) in addition to imatinib, providers have more options for the treatment of chronic-phase CML (CML-CP) in children. The second-generation TKIs approved for use in children, nilotinib and dasatinib, have higher response rates than first-generation imatinib; however, overall survival rates appear to be the same. Even more options may soon become available with ongoing investigations into the use of bosutinib and ponatinib and other new agents in children. Possible long-term side effects of TKIs, including growth failure, should be carefully acknowledged by the treating provider. Although these known associations may not preclude treatment, providers should be aware of them to guide their management of pediatric patients with CML being treated long term with TKI therapy. Treatment-free remission is a desired goal for pediatric patients and providers alike, but current recommendations are for attempts at achieving this to be restricted to clinical study settings.

Treatment of acute myeloid leukemia in children: A practical perspective.

Pediatric acute myeloid leukemia (AML) is a heterogeneous disease that requires a multifaceted treatment approach. Although outcomes for low-risk AML have improved significantly over recent decades, high-risk AML continues to be associated with an adverse prognosis. Recent advances in molecular diagnostics, risk stratification, and supportive care have contributed to improvements in outcomes in pediatric AML. Targeted approaches, for example, the use of tyrosine kinase inhibitors to treat FLT3-ITD AML, offer promise and are currently undergoing clinical investigation in pediatric patients. New approaches to hematopoietic stem cell transplantation, including the use of haploidentical donors, are significantly expanding donor options for patients with high-risk AML. This review provides an overview of recent advances in the treatment of pediatric AML that are likely to have clinical impact and reshape the standard of care.

Clinical features of secondary acute myeloid leukemia in children

Background. Secondary malignancies in pediatric cancer survivors is an actual problem in modern oncopediatry. Alkylating agents and topoisomerase II inhibitors used for primary tumors treatment, induce secondary acute myeloid leukemia (sAML), which treatment results are unsatisfactory.Objective. By predicating on literature and own data to evaluate clinical and biologic features and therapeutic potential of pediatric sAML.Materials and methods. Six patients (age 7–16 years) with sAML were enrolled the study from June 1998 to December 2016. Follow up until September 2020. Primary tumors, which therapy could induce sAML were acute lymphoblastic leukemia, Burkitt lymphoma, germ cell tumor, osteosarcoma, nephroblastoma.Results and conclusion. From 6 patients, included in the study, 2 are alive (+58 and +67 months after allogenic stem cell transplantation), that match global data. Fludarabine-containing regimens and allogeneic hematopoietic stem cell transplant could be a method of choice for this unfavorable group of patients.

Childhood Leukemia- A study on Novel Treatment for Acute Myeloid Leukemia in Children

Intense myeloid leukemia is a heterogeneous illness that represents around 20% of intense leukemias in youngsters and teenagers. In spite of the absence of focused treatment for most subtypes and a deficiency of new operators, endurance rates have reached around 60% for kids rewarded on clinical preliminaries in created nations. A large portion of the advances have been practiced by better hazard arrangement, the execution of brilliant strong consideration measures, adjustment of treatment based on every patient's reaction to treatment, and upgrades in allogeneic hematopoietic undifferentiated organism transplantation. Notwithstanding, it is far-fetched that further gains can be made through these measures alone. In such manner, high-goal, genome-wide examinations have prompted more noteworthy comprehension of the pathogenesis of this illness and the distinguishing proof of sub-atomic variations from the norm that are possible focuses of new treatments. The advancement of molecularly focused on operators, some of which are as of now in clinical preliminaries, holds extraordinary guarantee for what's to come.

The outcomes of relapsed acute myeloid leukemia in children: Results from the Japanese Pediatric Leukemia/Lymphoma Study Group AML‐05R study

The prognosis of children with acute myeloid leukemia (AML) has improved with the efficacy of hematopoietic cell transplantation (HCT) as a second-line therapy and improvements in supportive care following anthracycline- and cytarabine-based chemotherapy; however, the outcomes of children with relapsed AML still remain unsatisfactory. In order to identify prognostic factors and improve their prognosis, we analyzed 111 patients who relapsed after treatment with the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 protocol and who were registered in the retrospective JPLSG AML-05R study. The 5-year overall survival rate was 36.1%. The major determinant of survival was duration from the diagnosis to relapse. The mean duration in the nonsurviving group (10.1 ± 4.1 months) was shorter than that in the surviving group (16.3 ± 8.3 months) (P<.01). Moreover, achieving a second complete remission (CR2) prior to HCT was associated with a good prognosis (P<.01). Etoposide, cytarabine, and mitoxantrone (ECM)- or fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG)-based regimens were therefore recommended for reinduction therapy (P<.01). A genetic analysis also revealed the prognostic significance of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication as a poor prognostic marker (P=.04) and core binding factor-AML, t(8;21), and inv(16) as good prognostic markers (P<.01). Achieving a CR2 prior to HCT is important in order to improve the prognosis of relapsed pediatric AML. Recent molecular targeted therapies, such as FLT3 inhibitors, may contribute to overcome their prognoses. Larger prospective investigations are necessary to establish individualized treatment strategies for patients with relapsed childhood AML.

Targeted drugs in the treatment of acute myeloid leukemia in children

The recent chemotherapeutic approaches to acute myeloid leukemia (AML) management reached the limits, achieving overall survival rate of approximately 70 %. An intensification of chemotherapeutic regimens is barely possible due to high level of toxicity and risk of lifethreatening complications. The modernization of program therapy of AML involves the clinical application of achievements in molecular biology, immunology and cytogenetic of the tumor cell. The researches in fundamental oncology revealed the phases of leukemogenesis and defined selective ways of targeted therapy in the treatment of AML.

Uncommon cytogenetic abnormalities identifying high-risk acute myeloid leukemia in children.

Pediatric acute myeloid leukemia (AML) represents an aggressive disease and is the leading cause of childhood leukemic mortality. The genomic landscape of pediatric AML has been recently mapped and redefined thanks to large-scale sequencing efforts. Today, understanding how to incorporate the growing list of genetic lesions into a risk stratification algorithm for pediatric AML is increasingly challenging given the uncertainty regarding the prognostic impact of rare lesions. Here we review some uncommon cytogenetic lesions to be considered for inclusion in the high-risk groups of the next pediatric AML treatment protocols. We describe their main clinical characteristics, biological background and outcome. We also provide some suggestions for the management of these rare but challenging patients and some novel targeted therapeutic options.

Paediatric Strategy Forum for medicinal product development for acute myeloid leukaemia in children and adolescents: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration

PurposeThe current standard-of-care for front-line therapy for acute myeloid leukaemia (AML) is a combination of an anthracycline with cytarabine resulting in significant short-term and long-term toxicity, but still approximately 40% of children relapse. Therefore, there is a major need to accelerate the introduction of innovative medicines into the therapy, yet drug development continues to be adult-focused. Furthermore, there are major differences, including differing profiles of genetic abnormalities, making clinical development of adult AML drugs in children problematic. The large number of competing agents in rare patient populations requires coordinated prioritisation, within the global regulatory framework and cooperative group initiatives. MethodsTo address these issues, the fourth multi-stakeholder Paediatric Strategy Forum focused on AML in children and adolescents. ResultsEight classes of medicinal products were discussed at the Forum: FLT3, IDH1&2, checkpoint, cell signalling and HDAC inhibitors, monoclonal antibodies, bispecific T cell engagers and ADCs as well as other cytotoxics. CD123 is a high priority target for immunotherapies, and the paediatric development of CD123-targeted drugs should be accelerated as a proof-of-concept. Efforts must be coordinated, however, as there are a limited number of studies that can be delivered. The studies of FLT3 inhibitors included in agreed paediatric investigation plans (PIPs) present challenges to be completed because they would require enrolment of a larger number of patients than actually exist. A consensus was developed by industry and academia of optimised clinical trials, which could be included in PIPs. For AML with rare mutations that are more frequent in adolescents than in children, adult trials should enrol adolescents and when scientifically justified, efficacy data could be extrapolated from adolescent and adult data to younger children. There is also an important need to standardise internationally and validate methodologies and definitions of minimal residual disease, so that it can be used as a new response criterion. Industry supported, academic sponsored platform trials with compounds from different pharmaceutical companies could identify products to be further developed in paediatric AML. The Leukaemia and Lymphoma Society PedAL/EUpAL initiative may fulfil these requirements and has the potential to be a major advance in the field. ConclusionThe initiatives created during the Forums will be continued as part of an ongoing process, aiming to accelerate drug development for children with AML and ultimately improve clinical outcomes.

Comparison of total body irradiation versus non-total body irradiation containing regimens for de novo acute myeloid leukemia in children.

With limited data comparing hematopoietic cell transplant outcomes between myeloablative total body irradiation (TBI) containing and non-TBI regimens in children with de novo acute myeloid leukemia, the aim of this study was to compare transplant-outcomes between these regimens. Cox regression models were used to compare transplant-outcomes after TBI and non-TBI regimens in 624 children transplanted between 2008 and 2016. Thirty two percent (n=199) received TBI regimens whereas 68% (n=425) received non-TBI regimens. Five-year non-relapse mortality was higher with TBI regimens (22% vs. 11%, P<0.0001) but relapse was lower (23% vs. 37%, P<0.0001) compared to non-TBI regimens. Consequently, overall (62% vs. 60%, P=1.00) and leukemia-free survival (55% vs. 52%, P=0.42) did not differ between treatment groups. Grade 2-3 acute graft versus host disease was higher with TBI regimens (56% vs. 27%, P<0.0001) but not chronic graft versus host disease. The 3-year incidence of gonadal or growth hormone deficiency was higher with TBI regimens (24% vs. 8%, P<0.001) but there were no differences in late pulmonary, cardiac or renal impairment. In the absence of a survival advantage, the choice of TBI or non-TBI regimen merits careful consideration with the data favoring non-TBI regimens to limit the burden of morbidity associated with endocrine dysfunction.

Outcome of Core Binding Factor Acute Myeloid Leukemia in Children: A Single-Center Experience

Childhood acute myeloid leukemia (AML) harboring core binding factor (CBF)-associated translocations are considered as a favorable cytogenetic subgroup. The 2 major subtypes of CBF-AML include t(8;21) and inversion of chromosome 16, accounting for ∼25% of patients. Because of expensive and toxic treatment, which may require hospitalization during the entire course of induction chemotherapy, most of the centers in Pakistan neither workup for this low-risk entity nor offer curative treatment. Therefore, we adopted an approach of screening AML cases for the presence of CBF with the rationale of offering curative treatment to this subgroup. Data of 244 cases were reviewed, and translocations were found in 72 (34%) patients among them, 59 (82%) had t(8;21) and 13 (18%) showed inversion of chromosome 16. The event-free survival with and without abandonment was 36% and 40%, respectively. Among 44 patients who completed treatment, 26 (59%) are leukemia-free, while 18 (41%) relapsed. None of the relapsed patients received salvage chemotherapy or hematopoietic stem cell transplant. Treatment-related mortality and abandonment was found in 24% and 10% of patients, respectively. The frequency of CBF-AML is higher in our study; however, poor outcome demands holistic measures in supportive care to improve the survival.

Research status of and treatment progress in chronic myeloid leukemia in children

慢性粒细胞白血病（CML）在儿童中相对罕见，其临床表现、免疫表型及遗传学特征与成年患者存在差异。CML患儿处于特殊的成长时期，可能接受长达数十年的酪氨酸抑制剂（TKI）治疗，不良反应发生率可能高于成年患者。与成年CML患者相比，首诊CML患儿的TKI药物选择仍需要探讨，造血干细胞移植的地位存在争议。本文对儿童CML的研究现状、TKI时代患儿用药、疗效监测及移植时机选择进行综述。.

Gemase for treatment of intraretinal hemorrhages and hemophthalmia at thrombocytopenia due to acute myeloid leukemia in children

Intraretinal hemorrhages are the most common eye lesion in patients with hemoblastosis. Such patients have lower hemoglobin and platelet counts than those who haven’t hemorrhages. Hemophthalmia is the penetration of blood into the vitreous body or into one of the spaces formed around it. The reason for this may be vessels damage of the retina or newly formed vessels of the retina, that are more fragile compared to normal. Thrombocytopenia is one of the most common hematological symptoms in different blood diseases. Thrombocytopenia is a significant decrease in the number of circulating platelets (less than 100 × 109 /l), which leads to bleeding. Ophthalmic problems can occur in acute leukemia with thrombocytopenia, which can affect any anatomical structures of the eye. The relationship between hematological parameters and the nature of changes in the fundus has been established. The article provides analysis of two clinical cases of hemophthalmia in pediatric patients with acute myeloid leukemia and description of positive dynamics on therapy with Gemase. Parents gave their consent to use information about the child, including fotos, in the article.

Gemase for treatment of intraretinal hemorrhages and hemophthalmia at thrombocytopenia due to acute myeloid leukemia in children

Intraretinal hemorrhages are the most common eye lesion in patients with hemoblastosis. Such patients have lower hemoglobin and platelet counts than those who haven’t hemorrhages. Hemophthalmia is the penetration of blood into the vitreous body or into one of the spaces formed around it. The reason for this may be vessels damage of the retina or newly formed vessels of the retina, that are more fragile compared to normal. Thrombocytopenia is one of the most common hematological symptoms in different blood diseases. Thrombocytopenia is a significant decrease in the number of circulating platelets (less than 100 × 109 /l), which leads to bleeding. Ophthalmic problems can occur in acute leukemia with thrombocytopenia, which can affect any anatomical structures of the eye. The relationship between hematological parameters and the nature of changes in the fundus has been established. The article provides analysis of two clinical cases of hemophthalmia in pediatric patients with acute myeloid leukemia and description of positive dynamics on therapy with Gemase. Parents gave their consent to use information about the child, including fotos, in the article.

Chronic Myeloid Leukemia in Children: Challenges and Opportunities : Based on 7th Dr. I. C. Verma Excellence Award for Young Pediatricians Delivered as Oration on 29th Sept. 2019.

Treatment with tyrosine kinase inhibitors (TKI) is an effective therapy for children and adolescents with chronic phase of chronic myeloid leukemia (CML). For the majority of patients with CML in low- and middle-income countries (LMIC), imatinib is the TKI of choice for reasons of cost, availability, and experience. Children are exposed to therapy for a greater proportion of their lifetime as compared to adults. The adverse effects of prolonged administration of TKI is a subject of ongoing research, as more experience is collected. Therapy with TKI is currently considered to be life-long. Trials on stopping treatment are ongoing to explore if it may be feasible in selected patients, as reported in adults. Growth-failure is a concerning adverse effect. Currently, it seems unclear if the final height attained is within the expected range of the mid-parenteral height and growth standards. Whether the children will achieve a normal height at the end of their growth potential or remain below the predicted range is critical to decide if therapeutic interventions (E.g., growth hormone therapy, or interruption in TKI) should be considered during the period of growth potential. Research on CML in children is at a relatively slow pace, largely due to the rarity of the disease. This provides a unique opportunity for research in population-dense LMICs, as several tertiary centers tend to have a sizable cohort of children and adolescents with CML on follow-up. This narrative summarises the challenges and opportunities in dealing with CML in children, particularly in reference to a center in LMIC.