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Severe asymptomatic hypophosphataemia in a child with T-acute lymphoblastic leukaemia

Zakaria NH, Sthaneshwar P, Shanmugam H

Malays J Pathol, 2017 Dec;39(3):317-320.
PMID: 29279597 MyJurnal

Hypophosphataemia is a metabolic disorder that is commonly encountered in critically ill patients. Phosphate has many roles in physiological functions, thus the depletion of serum phosphate could lead to impairment in multiple organ systems, which include the respiratory, cardiovascular, neurological and muscular systems and haematological and metabolic functions. Hypophosphataemia is defined as plasma phosphate level below 0.80 mmol per litre (mmol/L) and can be further divided into subgroups of mild (plasma phosphate of 0.66 to 0.79 mmol/L), moderate (plasma phosphate of 0.32 to 0.65 mmol/L) and severe (plasma phosphate of less than 0.32 mmol/L). The causes of hypophosphataemia include inadequate phosphate intake, decreased intestinal absorption, gastrointestinal or renal phosphate loss, and redistribution of phosphate into cells. Symptomatic hypophosphataemia associated with haematological malignancies has been reported infrequently. We report here a case of asymptomatic severe hypophosphataemia in a child with acute T-cell lymphoblastic leukaemia. A 14-year-old Chinese boy was diagnosed to have acute T cell lymphoblastic leukaemia (ALL). His serum biochemistry results were normal except inorganic phosphate and lactate dehydrogenase levels. The serum inorganic phosphate level was 0.1mmol/L and the level was low on repeated analysis. The child had no symptoms related to low phosphate levels. The possible causes of low phosphate were ruled out and urine Tmp/GFR was normal. Chemotherapy regime was started and the serum phosphate levels started to increase. Hypophosphataemia in leukaemia was attributed to shift of phosphorus into leukemic cells and excessive cellular phosphate consumption by rapidly proliferating cells. Several reports of symptomatic hypophosphataemia in myelogenous and lymphoblastic leukaemia in adults have been reported. To our knowledge this is the first case of severe asymptomatic hypophosphataemia in a child with ALL.

Matched MeSH terms: Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/blood; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/complications*
Eosinophilic myocarditis mimicking acute coronary syndrome in a young man with T-lymphoblastic lymphoma and hypereosinophilia

Raffali MAA, Boon Cong B, Muhammad SF, Che Hassan HH

BMJ Case Rep, 2023 Sep 25;16(9).
PMID: 37748814 DOI: 10.1136/bcr-2023-255396

A man in his 20s with underlying chemorefractory primary T-lymphoblastic lymphoma and hypereosinophilia developed acute chest pain in the ward after readmission for disease progression. ECG showed widespread ST depression and serum troponin was markedly elevated. Transthoracic echocardiography showed diffused thrombus deposition with preserved ejection fraction consistent with eosinophilic myocarditis. The patient ultimately succumbed to the disease, after complications with severe hospital-acquired pneumonia.

Matched MeSH terms: Precursor T-Cell Lymphoblastic Leukemia-Lymphoma*
Zerumbone induces apoptosis in T-acute lymphoblastic leukemia cells

Abdelwahab SI, Abdul AB, Mohan S, Taha MM, Syam S, Ibrahim MY, et al.

Leuk. Res., 2011 Feb;35(2):268-71.
PMID: 20708800 DOI: 10.1016/j.leukres.2010.07.025

Zerumbone (ZER) is a potential anticancer natural compound, isolated from Zingiber zerumbet Smith. In this investigation, the anticancer properties of ZER were evaluated on cancer cells of T-acute lymphoblastic leukemia, CEM-ss. The results showed that ZER has cytotoxic effect against CEM-ss cells with an IC(50) of 8.4 ± 1.9 μg/ml (coefficient of variation < 30%). Comparatively, 5-fluorouracil (positive control), imposed an inhibitory effect on CEM-ss cells with an IC(50) of 1.94 ± 0.06 μg/ml. Scanning electron microscopy (SEM) results revealed abnormalities such as membrane blebbing, holes and cytoplasmic extrusions, all of which are characteristics of apoptosis. In addition, ZER has increased the number of TUNEL-positive stain and the cellular level of caspase-3, the hallmarks of apoptosis, on treated CEM-ss cells. It could be concluded that, ZER was able to produce apoptosis on T-acute lymphoblastic leukemia, CEM-ss. The current findings suggest that ZER might be helpful for improving the usefulness of anticancer agents in the therapy of leukemia.

Matched MeSH terms: Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology*
Fulltext Whole-genome noncoding sequence analysis in T-cell acute lymphoblastic leukemia identifies oncogene enhancer mutations

Hu S, Qian M, Zhang H, Guo Y, Yang J, Zhao X, et al.

Blood, 2017 Jun 15;129(24):3264-3268.
PMID: 28408461 DOI: 10.1182/blood-2017-03-771162

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Matched MeSH terms: Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics*
Fulltext Anticancer Potential of Damnacanthal and Nordamnacanthal from Morinda elliptica Roots on T-lymphoblastic Leukemia Cells

Latifah SY, Gopalsamy B, Abdul Rahim R, Manaf Ali A, Haji Lajis N

Molecules, 2021 Mar 12;26(6).
PMID: 33808969 DOI: 10.3390/molecules26061554

BACKGROUND: This study reports on the cytotoxic properties of nordamnacanthal and damnacanthal, isolated from roots of Morinda elliptica on T-lymphoblastic leukaemia (CEM-SS) cell lines.
METHODS: MTT assay, DNA fragmentation, ELISA and cell cycle analysis were carried out.
RESULTS: Nordamnacanthal and damnacanthal at IC50 values of 1.7 μg/mL and10 μg/mL, respectively. At the molecular level, these compounds caused internucleosomal DNA cleavage producing multiple 180-200 bp fragments that are visible as a "ladder" on the agarose gel. This was due to the activation of the Mg2+/Ca2+-dependent endonuclease. The induction of apoptosis by nordamnacanthal was different from the one induced by damnacanthal, in a way that it occurs independently of ongoing transcription process. Nevertheless, in both cases, the process of dephosphorylation of protein phosphates 1 and 2A, the ongoing protein synthesis and the elevations of the cytosolic Ca2+ concentration were not needed for apoptosis to take place. Nordamnacanthal was found to have a cytotoxic effect by inducing apoptosis, while damnacanthal caused arrest at the G0/G1 phase of the cell cycle.
CONCLUSION: Damnacanthal and nordamnacanthal have anticancer properties, and could act as potential treatment for T-lymphoblastic leukemia.

Matched MeSH terms: Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy*; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism
Miltefosine suppression of Pten null T-ALL leukemia via β-catenin degradation through inhibition of pT308-Akt and TGFβ1/Smad3

Zhang Y, Lee S, Xu W

Biochem Biophys Res Commun, 2020 04 16;524(4):1018-1024.
PMID: 32063363 DOI: 10.1016/j.bbrc.2020.02.021

Pten deletion in the hematopoietic stem cells (HSC) causes a myeloproliferative disorder, which may subsequently develop into a T-cell acute lymphoblastic leukemia (T-ALL). β-catenin expression was dramatically increased in the c-KitmidCD3+Lin- leukemia stem cells (LSC) and was critical for T-ALL development. Therefore, the inactivation of β-catenin in LSC may have a potential to eliminate the LSC. In this study, we investigated the mechanism of enhancement of the β-catenin expression and subsequently used a drug to inactivate β-catenin expression in T-ALL. Western blot (WB) analysis revealed an increased level of β-catenin in the leukemic cells, but not in the pre-leukemic cells. Furthermore, the WB analysis of the thymic cells from different stages of leukemia development showed that increased expression of β-catenin was not via the pS9-GSK3β signaling, but was dependent on the pT308-Akt activation. Miltefosine (Hexadecylphosphocholine) is the first oral anti-Leishmania drug, which is a phospholipid agent and has been shown to inhibit the PI3K/Akt activity. Treatment of the PtenΔ/Δ leukemic mice with Miltefosine for different durations demonstrated that the pT308-Akt and the β-catenin expressions were inhibited in the leukemia blast cells. Miltefosine treatment also suppressed the TGFβ1/Smad3 signaling pathway. Analysis of TGFβ1 in the sorted subpopulations of the blast cells showed that TGFβ1 was secreted by the CD3+CD4- subpopulation and may exert effects on the subpopulations of both CD3+CD4+ and CD3+CD4- leukemia blast cells. When a TGFβR1 inhibitor, SB431542 was injected into the PtenΔ/Δ leukemic mice, the Smad3 and β-catenin expressions were down-regulated. On the basis of the results, we conclude that Miltefosine can suppress leukemia by degrading β-catenin through repression of the pT308-Akt and TGFβ1/Smad3 signaling pathways. This study demonstrates a possibility to inhibit Pten loss-associated leukemia genesis via targeting Akt and Smad3.

Matched MeSH terms: Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy*; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism
Immunoglobulin Heavy Chain Gene Rearrangement in Non B-cell Haematological Malignancies

Noor Haslina MN, Marini R, Rosnah B, Shafini MY, Wan Haslindawani WM, Mohd Nazri H, et al.

West Indian Med J, 2013 Nov;62(8):701-4.
PMID: 25014854 DOI: 10.7727/wimj.2013.253

OBJECTIVE: Clonality detection through amplifying immunoglobulin heavy chain (IGH) gene rearrangements by polymerase chain reaction (PCR) is a useful tool in diagnosis of various B-lymphoid malignancies. Immunoglobulin heavy chain gene rearrangement can be an optimal target for clonality detection in B-lymphoid malignancies. In the present study, we evaluated the presence of IGH gene rearrangement in non B-cell haemato-oncology patients including T-cell acute lymphoblastic leukaemia (T-ALL), acute myeloblastic leukaemia (AML) and biphenotypic leukaemia.
MEHTODS: We studied 18 cases of haematological malignancies which comprised five patients with T-ALL, 12 patients with AML and one with biphenotypic leukaemia.
RESULTS: We found that the incidence of IGH gene rearrangement in T-ALL and AML were three (60%) and two (16.7%), respectively. The patient with biphenotypic leukaemia was negative for IGH gene rearrangement.
CONCLUSION: Immunoglobulin gene rearrangement, which occurs in almost all haematological malignancies of B-cell lineage, also presents in a very small proportion of T-cell or myeloid malignancies.

Matched MeSH terms: Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Intracellular vincristine levels in lymphoblasts affect treatment outcome in childhood B-lymphoblastic leukaemia: Ma-Spore ALL 2010 study

Jiang N, Wang L, Xiang X, Li Z, Chiew EKH, Koo YM, et al.

Br J Clin Pharmacol, 2021 Apr;87(4):1990-1999.
PMID: 33037681 DOI: 10.1111/bcp.14596

AIMS: Vincristine (VCR) is a key drug in the successful multidrug chemotherapy for childhood acute lymphoblastic leukaemia (ALL). However, it remains unclear how VCR pharmacokinetics affects its antileukaemic efficacy. The objective of this study is to explore the VCR pharmacokinetic parameters and intracellular VCR levels in an up-front window of Ma-Spore ALL 2010 (MS2010) study.
METHODS: We randomised 429 children with newly diagnosed ALL to 15-minute vs 3-hour infusion for the first dose of VCR to study if prolonging the first dose of VCR infusion improved response. In a subgroup of 115 B-ALL and 20 T-ALL patients, we performed VCR plasma (n = 135 patients) and intracellular (n = 66 patients) pharmacokinetic studies. The correlations between pharmacokinetic parameters and intracellular VCR levels with early treatment response, final outcome and ABCB1 genotypes were analysed.
RESULTS: There was no significant difference between 15-minute and 3-hour infusion schedules in median Day 8 peripheral or bone marrow blast response. Plasma VCR pharmacokinetic parameters did not predict outcome. However, in B-ALL, Day 33 minimal residual disease (MRD) negative patients and patients in continuous complete remission had significantly higher median intracellular VCR24h levels (P = .03 and P = .04, respectively). The median VCR24h intracellular levels were similar among the common genetic subtypes of ALL (P = .4). Patients homozygous for wild-type ABCB1 2677GG had significantly higher median intracellular VCR24h (P = .04) than 2677TT.
CONCLUSION: We showed that in childhood B-ALL, the intracellular VCR24h levels in lymphoblasts affected treatment outcomes. The intracellular VCR24h level was independent of leukaemia subtype but dependent on host ABCB1 G2677T genotype.

Matched MeSH terms: Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Fulltext Early lineage switch from T-acute lymphoblastic leukaemia to common B-ALL

Hafiza, A., Azma, R.Z., Azura, A.H., Azlin, I., Zarina, A.L., Hamidah, N.H.

Medicine & Health, 2011;6(2):131-138.
MyJurnal

Leukaemic stem cells have heterogenous differentiation potential. The immunophenotypes of blast cells are usually consistent throughout the disease course even at relapse. Rarely, blast cells may undergo a ‘lineage switch’ during the course of disease especially during relapse. We would like to highlight such a case in a 10- year old boy who presented with a two weeks history of lethargy, poor appetite, low grade fever, respiratory distress, cardiac failure, generalized oedema and hepatosplenomegaly. Full blood count showed a leucocyte count of 41.5x10 9 /L and platelet count of 37x10 9 /L. The peripheral blood film showed presence of numerous blast cells. Bone marrow aspiration revealed a hypercellular marrow, which consisted of mainly blast cells with high nuclear to cytoplasmic ratio and inconspicuous nucleoli. Immunophenotyping and cytochemistry results were consistent with the diagnosis of Tcell acute lymphoblastic leukaemia. The patient achieved remission after treatment with UK ALL 97 protocol, regime B chemotherapy. However, he relapsed seven months after the initial diagnosis with 26% blast cells in the bone marrow aspirate. The majority was L1 blast cells admixed with some L2 blast cells. Immunophenotyping was consistent with common precursor B acute lymphoblastic leukaemia. The treatment was changed to a more lineage specific chemotherapy. Nonetheless, the patient never achieved remission and was planned for palliative management. This case illustrated a unique and rare case of rapid lineage switch from T-cell acute lymphoblastic leukaemia to common precursor B-cell acute lymphoblastic leukaemia.

Matched MeSH terms: Precursor T-Cell Lymphoblastic Leukemia-Lymphoma