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British Journal of Haematology Jul 2019While survival in paediatric acute lymphoblastic leukaemia (ALL) is excellent, survival following relapse is poor. Previous studies suggest proteasome inhibition with... (Clinical Trial)
Clinical Trial
While survival in paediatric acute lymphoblastic leukaemia (ALL) is excellent, survival following relapse is poor. Previous studies suggest proteasome inhibition with chemotherapy improves relapse ALL response rates. This phase 2 Children's Oncology Group study tested the hypothesis that adding the proteasome inhibitor bortezomib to chemotherapy increases complete response rates (CR2). Evaluable patients (n = 135, 103 B-ALL, 22 T-ALL, 10 T-lymphoblastic lymphoma) were treated with reinduction chemotherapy plus bortezomib. Overall CR2 rates were 68 ± 5% for precursor B-ALL patients (<21 years of age), 63 ± 7% for very early relapse (<18 months from diagnosis) and 72 ± 6% for early relapse (18-36 months from diagnosis). Relapsed T-ALL patients had an encouraging CR2 rate of 68 ± 10%. End of induction minimal residual disease (MRD) significantly predicted survival. MRD negative (MRDneg; MRD <0·01%) rates increased from 29% (post-cycle 1) to 64% following cycle 3. Very early relapse, end-of-induction MRDneg precursor B-ALL patients had 70 ± 14% 3-year event-free (EFS) and overall survival (OS) rates, vs. 3-year EFS/OS of 0-3% (P = 0·0001) for MRDpos (MRD ≥0·01) patients. Early relapse patients had similar outcomes (MRDneg 3-year EFS/OS 58-65% vs. MRDpos 10-19%, EFS P = 0·0014). These data suggest that adding bortezomib to chemotherapy in certain ALL subgroups, such as T-cell ALL, is worthy of further investigation. This study is registered at http://www.clinical.trials.gov as NCT00873093.
Topics: Adolescent; Adult; Bortezomib; Child; Child, Preschool; Disease-Free Survival; Female; Humans; Infant; Male; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Survival Rate; Time Factors
PubMed: 30957229
DOI: 10.1111/bjh.15919 -
JAMA May 2023
Topics: Skiing; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recovery of Function
PubMed: 37115529
DOI: 10.1001/jama.2023.7072 -
The Journal of Pediatrics May 2021
Topics: Child, Preschool; Diagnosis, Differential; Facial Neoplasms; Female; Forehead; Humans; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Skin Neoplasms
PubMed: 33444642
DOI: 10.1016/j.jpeds.2021.01.001 -
Journal of the College of Physicians... Feb 2018Lymphoid (or lymphocytic/lymphoblastic) leukemia, one of two major types of leukemias (lymphoid and myeloid), is divided into two subtypes, acute lymphoid leukemia (ALL)... (Review)
Review
Lymphoid (or lymphocytic/lymphoblastic) leukemia, one of two major types of leukemias (lymphoid and myeloid), is divided into two subtypes, acute lymphoid leukemia (ALL) and chronic lymphocytic leukemia (CLL), depending on the maturation stage and speed of multiplication of the bone marrow lymphocytes. Early diagnosis and treatment can make the difference between life and death. Advancements in the field of proteomics may allow the development of early biomarkers and more effective agents to combat both these types of cancer, and to better understand the underlying mechanisms of the disease. The aim of this review was to elucidate the pathophysiology of lymphocytic leukemia using cancer proteomics techniques from 2007 until 2017. Only relevant original research articles archived in the Science Direct, PubMed and/or the Google Scholar databases within this period were included, which were a total of 30 studies. The role of proteomes in the detection, diagnosis and treatment of ALL and CLL was examined separately. Overall, the findings of this study confirm the viability of proteome analysis in profiling lymphocytic leukemia; and highlight novel leukemia biomarkers and potential therapeutic targets.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proteome; Proteomics
PubMed: 29394974
DOI: 10.29271/jcpsp.2018.02.133 -
Future Oncology (London, England) 2015The occurrence of venous thromboembolism (VTE) in acute lymphocytic leukemia patients receiving L-asparaginase therapy may cause significant morbidity, neurological... (Review)
Review
The occurrence of venous thromboembolism (VTE) in acute lymphocytic leukemia patients receiving L-asparaginase therapy may cause significant morbidity, neurological sequela and possibly worse outcomes. The prophylactic use of antithrombin infusion (to keep antithrombin activity >60%) or low molecular weight heparin (LMWH) may reduce the risk of VTE. The decision to continue L-asparaginase therapy after the development of VTE should be based on anticipated benefits, severity of VTE and the ability to continue therapeutic anticoagulation. In patients receiving asparaginase rechallenge, the use of therapeutic LMWH, monitoring of anti-Xa level and antithrombin level are important. Novel oral anticoagulants are not dependent on antithrombin level, hence offer theoretical advantages over LMWH for the prevention and therapy of asparaginase-related VTE.
Topics: Antineoplastic Agents; Asparaginase; Disease Management; Humans; Incidence; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors; Venous Thromboembolism
PubMed: 26274336
DOI: 10.2217/fon.15.114 -
The Lancet. Haematology Oct 2021CNS relapse of acute lymphocytic leukaemia is difficult to treat. Durable remissions of relapsed or refractory B-cell acute lymphocytic leukaemia have been observed... (Clinical Trial)
Clinical Trial
CD19-targeted chimeric antigen receptor T-cell therapy for CNS relapsed or refractory acute lymphocytic leukaemia: a post-hoc analysis of pooled data from five clinical trials.
BACKGROUND
CNS relapse of acute lymphocytic leukaemia is difficult to treat. Durable remissions of relapsed or refractory B-cell acute lymphocytic leukaemia have been observed following treatment with CD19-directed chimeric antigen receptor (CAR) T cells; however, most trials have excluded patients with active CNS disease. We aimed to assess the safety and activity of CAR T-cell therapy in patients with a history of CNS relapsed or refractory B-cell acute lymphocytic leukaemia.
METHODS
In this post-hoc analysis, we included 195 patients (aged 1-29 years; 110 [56%] male and 85 [44%] female) with relapsed or refractory CD19-positive acute lymphocytic leukaemia or lymphocytic lymphoma from five clinical trials (Pedi CART19, 13BT022, ENSIGN, ELIANA, and 16CT022) done at the Children's Hospital of Philadelphia (Philadelphia, PA, USA), in which participants received CD19-directed CAR T-cell therapy between April 17, 2012, and April 16, 2019. The trials required control of CNS disease at enrolment and infusion and excluded treatment in the setting of acute neurological toxic effects (>grade 1 in severity) or parenchymal lesions deemed to increase the risk of neurotoxicity. 154 patients from Pedi CART19, ELIANA, ENSIGN, and 16CT022 received tisagenlecleucel and 41 patients from the 13BT022 trial received the humanised CD19-directed CAR, huCART19. We categorised patients into two strata on the basis of CNS status at relapse or within the 12 months preceding CAR T-cell infusion-either CNS-positive or CNS-negative disease. Patients with CNS-positive disease were further divided on the basis of morphological bone marrow involvement-either combined bone marrow and CNS involvement, or isolated CNS involvement. Endpoints were the proportion of patients with complete response at 28 days after infusion, Kaplan-Meier analysis of relapse-free survival and overall survival, and the incidence of cytokine release syndrome and neurotoxicity.
FINDINGS
Of all 195 patients, 66 (34%) were categorised as having CNS-positive disease and 129 (66%) as having CNS-negative disease, and 43 (22%) were categorised as having isolated CNS involvement. The median length of follow-up was 39 months (IQR 25-49) in the CNS-positive stratum and 36 months (18-49) in the CNS-negative stratum. The proportion of patients in the CNS-positive stratum with a complete response at 28 days after infusion was similar to that in the CNS-negative stratum (64 [97%] of 66 vs 121 [94%] of 129; p=0·74), with no significant difference in relapse-free survival (60% [95% CI 49-74] vs 60% [51-71]; p=0·50) or overall survival (83% [75-93] vs 71% [64-79]; p=0·39) at 2 years between the two groups. Overall survival at 2 years was significantly higher in patients with isolated CNS involvement compared with those with bone marrow involvement (91% [82-100] vs 71% [64-78]; p=0·046). The incidence and severity of neurotoxicity (any grade, 53 [41%] vs 38 [58%]; grade 1, 24 [19%] vs 20 [30%]; grade 2, 14 [11%] vs 10 [15%]; grade 3, 12 [9%] vs 6 [9%], and grade 4, 3 [2%] vs 2 [3%]; p=0·20) and cytokine release syndrome (any grade, 110 [85%] vs 53 [80%]; grade 1, 12 [9%] vs 2 [3%]; grade 2, 61 [47%] vs 38 [58%]; grade 3, 18 [14%] vs 7 [11%] and grade 4, 19 [15%] vs 6 [9%]; p=0·26) did not differ between the CNS-negative and the CNS-positive disease strata.
INTERPRETATION
Tisagenlecleucel and huCART19 are active at clearing CNS disease and maintaining durable remissions in children and young adults with CNS relapsed or refractory B-cell acute lymphocytic leukaemia or lymphocytic lymphoma, without increasing the risk of severe neurotoxicity; although care should be taken in the timing of therapy and disease control to mitigate this risk. These preliminary findings support the use of these CAR T-cell therapies for patients with CNS relapsed or refractory B-cell acute lymphocytic leukaemia.
FUNDING
Children's Hospital of Philadelphia Frontier Program.
Topics: Adolescent; Adult; Antigens, CD19; Central Nervous System Neoplasms; Child, Preschool; Female; Humans; Immunotherapy, Adoptive; Infant; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Chimeric Antigen; Recurrence; Young Adult
PubMed: 34560014
DOI: 10.1016/S2352-3026(21)00238-6 -
Current Hematologic Malignancy Reports Jun 2017Most drugs used in standard regimens for acute lymphoblastic leukemia (ALL) were developed more than 30 years ago. Since that time, several new drugs have been... (Review)
Review
Most drugs used in standard regimens for acute lymphoblastic leukemia (ALL) were developed more than 30 years ago. Since that time, several new drugs have been developed and incorporated into ALL treatment. In spite of this, novel therapeutic approaches are still needed to improve outcomes for high-risk or relapsed ALL. This manuscript discusses newer treatment strategies, including purine nucleoside analogs, monoclonal antibodies, antibody drug conjugates, mammalian target of rapamycin (mTOR) inhibitors, proteasome inhibitors, histone deacetylase (HDAC) inhibitors, hypomethylating agents, spleen tyrosine kinase inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibitors, anti-programmed cell death protein (anti-PD-1) antibodies, mitogen-activated protein kinase (MEK) inhibitors, CXCR4 antagonists, poly (ADP-ribose) polymerase (PARP) inhibitors, and FMS-like tyrosine kinase 3 (FLT3) inhibitors. Additionally, this manuscript discusses the impact of diagnostic approaches on management of ALL. Specifically, minimal residual disease is increasingly felt to be important and will likely dramatically impact the care of ALL patients in the near future.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Clinical Trials as Topic; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Humans; Immunoconjugates; Molecular Targeted Therapy; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proteasome Inhibitors; Protein Kinase Inhibitors; Signal Transduction; Treatment Outcome
PubMed: 28353016
DOI: 10.1007/s11899-017-0380-3 -
Veterinary Pathology Jan 2018Leukemia is broadly divided into acute and chronic lymphocytic and myeloid types based on the proportion of blasts, morphology of cells, and expression of specific...
Leukemia is broadly divided into acute and chronic lymphocytic and myeloid types based on the proportion of blasts, morphology of cells, and expression of specific antigens on neoplastic cells. Classifying leukemia in horses can be challenging if blasts predominate and since few antibodies to identify cell types are available. The objective of this study was to describe in detail the clinical and pathologic features of acute leukemia in horses. Twelve horses ranging from 0.2 to 25.9 years of age were diagnosed with acute leukemia. Six cases were classified as acute lymphocytic leukemia (ALL) based on predominance of blasts, lack of granulocytic or monocytic differentiation, and detection of CD3, CD20, and/or CD79a antigens by immunohistochemistry. Six other cases were classified as acute myeloid leukemia (AML) with myelomonocytic ( n = 4), basophilic ( n = 1), and eosinophilic ( n = 1) differentiation based on > 20% bone marrow blasts and partial leukocytic differentiation. Reactivity with antibodies to Iba-1/AIF-1, CD172a, and CD163 was determined for all cases of AML. Eleven horses had thrombocytopenia, 10 had neutropenia, 8 had anemia, all had blasts on blood films, and none had leukocytosis. Ten horses had increased serum acute phase proteins. Bone marrow cellularity ranged from 30% to 100%, and the proportion of blasts ranged from 80% to 100% and 30% to 60% in ALL and AML, respectively. Horses were severely ill at diagnosis and euthanized within days or weeks. Unique features of acute leukemia in horses compared to other species were variable lymphocyte antigen expression (ALL) and frequent inflammation (ALL and AML).
Topics: Animals; Disease Progression; Horse Diseases; Horses; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thrombocytopenia
PubMed: 28812528
DOI: 10.1177/0300985817720983 -
Acta Haematologica 2018In 1963 Jean Bernard introduced the concept of "geographic hematology" and distinguished 2 branches, i.e., "ethnic hematology," which deals with differences between... (Review)
Review
In 1963 Jean Bernard introduced the concept of "geographic hematology" and distinguished 2 branches, i.e., "ethnic hematology," which deals with differences between populations, and "environmental hematology," which considers factors such as food habits, infections, and others. Both of these branches have implications in the distribution of hematological diseases worldwide. In comparison with Caucasian populations, in Mexico a significantly higher prevalence of acute lymphoblastic, acute promyelocytic, and acute megakaryoblastic leukemias has been described. The rate of chronic myeloid leukemia seems to be as high as that reported in Caucasian populations, while other myeloproliferative neoplasias are significantly less frequent in Mexico. Significantly lower prevalences of hairy cell leukemia, chronic lymphocytic leukemia, multiple myeloma, and Waldenström's macroglobulinemia have been reported from Mexico. Regrettably, the influence of drug companies interested in selling their new and expensive drugs has resulted in both overdiagnosis of some diseases and overidentification of the refractory forms of some of these conditions to justify the use of unnecessary drugs.
Topics: Hematologic Diseases; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Mexico; Myeloproliferative Disorders; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prevalence; Thalassemia
PubMed: 30227427
DOI: 10.1159/000491989 -
International Braz J Urol : Official... 2022
Topics: Child; Humans; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Testicular Neoplasms
PubMed: 36037260
DOI: 10.1590/S1677-5538.IBJU.2022.0318