leukaemia research reports

Leukemia Research Results and Study Updates

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Treatment options for people with acute myeloid leukemia (AML) have expanded yet again. On July 20, FDA approved quizartinib (Vanflyta) combined with chemotherapy as a first-line treatment for AML with a specific change in the FLT3 gene.

Giving the drug blinatumomab (Blincyto) after standard chemotherapy substantially increased survival for infants with an aggressive form of acute lymphoblastic leukemia (ALL), a recent study showed. If confirmed in larger studies, the treatment may become standard therapy for infants with ALL caused by KMT2A rearrangements.

Treatment with revumenib caused complete remission in about one-third of participants in an early-phase clinical trial involving patients who’d had many prior treatments. Revumenib is part of a new class of targeted drugs known as menin inhibitors.

An NCI-funded clinical trial has shown that treatment-related early deaths in people with a rare leukemia can be dramatically reduced. How did they do it? In part, by establishing a help desk staffed by experts in treating APL.

FDA has approved zanubrutinib (Brukinsa) for chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) based on results from two clinical trials. In both trials, the drug, which blocks a protein called BTK, was more effective and caused fewer side effects than other treatments.

The immunotherapy drug blinatumomab (Blincyto) extends life for people with acute lymphoblastic leukemia who are in remission, even those with no signs of disease after initial treatment, a trial has found.

For some people with acute myeloid leukemia (AML) that has a mutation in the IDH1 gene, combining ivosidenib (Tibsovo) with the chemotherapy drug azacitidine may be a new treatment option, according to results from a large clinical trial.

Removing immune cells called naive T cells from donated stem cells before they are transplanted may prevent chronic graft-versus-host disease (GVHD) in people with leukemia, a new study reports. The procedure did not appear to increase the likelihood of patients’ cancer returning.

A Children’s Oncology Group trial shows that the combination of all-trans retinoic acid and arsenic trioxide is highly effective in children with acute promyelocytic leukemia. The therapy avoids or minimizes the use of conventional chemotherapy.

The CAR T-cell therapy Tecartus has become the first such treatment approved by FDA to treat adults with acute lymphoblastic leukemia (ALL). The approval is for patients whose cancer has not responded to treatment or returned after treatment.

FDA has approved belumosudil (Rezurock) for the treatment of chronic graft-versus-host disease (GVHD). The approval covers the use of belumosudil for people 12 years and older who have already tried at least two other therapies.

FDA has approved a new form of asparaginase called Rylaze. The drug was developed to help alleviate shortages of Erwinia asparaginase, a key part of treatment for children and adults with acute lymphoblastic leukemia.

In a small study, vemurafenib (Zelboraf) and rituximab (Rituxan) helped 85% of participants stay in remission for nearly 3 years. The study involved 30 people with hairy cell leukemia that had come back after or had not responded to previous treatment.

People with blood cancers seem to be less protected by COVID-19 vaccines than those with other cancers and people without cancer, three new studies suggest. Experts believe this limited effectiveness is likely due to patients’ weakened immune systems.

For people with acute myeloid leukemia and related cancers, a new study shows whole-genome sequencing could replace a series of conventional tests used to help guide decisions about treatment.

The results of two trials establish blinatumomab (Blincyto) as a new standard treatment for children and young adults with high-risk relapsed B-cell acute lymphoblastic leukemia after remission has been achieved and before a stem cell transplant.

For adults with CML who are in a sustained deep molecular remission, stopping treatment with a tyrosine kinase inhibitor is safe and improves their quality of life, a study shows. But researchers cautioned that these patients must be closely monitored.

Two rediscovered drugs, bisantrene and brequinar, slowed the growth of acute myeloid leukemia in studies of mice. The drugs blocked the activity of a protein called FTO, killing cancer stem cells and helping the immune system attack the cancer.

Maintenance therapy with CC-486 extended overall survival of adults with the blood cancer acute myeloid leukemia (AML) in a large clinical trial. CC-486 is a pill form of another cancer therapy called azacitidine (Vidaza).

For children and young adults with certain relapsed B-cell acute lymphoblastic leukemia (B-ALL), the immunotherapy drug blinatumomab is superior to standard chemotherapy, an NCI-sponsored Children’s Oncology Group trial shows.

People with relapsed or refractory acute myeloid leukemia (AML) with FLT3 gene mutations treated with gilteritinib had improved survival, higher rates of remission, and fewer side effects than those treated with chemotherapy, a recent trial found.

Only 1.5% of children with acute lymphoblastic leukemia who skipped radiation had a recurrence in the central nervous system, according to a recent trial. The therapy, which is intended to prevent such a recurrence, can have devastating side effects.

The Food and Drug Administration has approved venetoclax (Venclexta) in combination with obinutuzumab (Gazyva) for the initial treatment of adults with chronic lymphocytic leukemia or small lymphocytic lymphoma.

New findings from a clinical trial of the drug tagraxofusp confirm its efficacy against the rare blood cancer blastic plasmacytoid dendritic cell neoplasm (BPDCN).

In this trial, patients with hairy cell leukemia who have disease-related symptoms that require treatment, and who have not been treated or have had only one prior treatment with cladribine, will be randomly assigned to receive cladribine with either concurrent rituximab or rituximab at least 6 months after completing cladribine therapy.

A clinical trial found that an intensive treatment regimen developed specifically for children with acute lymphoblastic leukemia is also effective for older adolescents and young adults with the disease.

FDA has approved venetoclax (Venclexta) and glasdegib (Daurismo) for use in people with acute myeloid leukemia aged 75 and older and those with health conditions that prevent them from receiving the intensive chemotherapy regimen that is the standard initial treatment.

Two new studies show how the drugs venetoclax (Venclexta) and azacitidine (Vidaza) team up to block the unique metabolism of leukemia stem cells and may explain why the drug combination is effective against acute myeloid leukemia.

A clinical trial showed that ibrutinib plus rituximab is superior to standard treatment for patients age 70 and younger with untreated chronic lymphocytic leukemia (CLL). Findings were announced at the American Society of Hematology annual meeting.

The FDA has approved moxetumomab pasudotox (Lumoxiti), a bacterial toxin–based drug, for the treatment of some patients with hairy cell leukemia (HCL). Moxetumomab is approved to treat patients with HCL who have already undergone at least two lines of standard treatments.

The FDA has approved ivosidenib (Tibsovo) for the treatment of adults with acute myeloid leukemia (AML) that has a specific mutation in a gene called IDH1. Ivosidenib becomes the first FDA-approved IDH1-targeted treatment.

FDA expanded the approval of venetoclax (Venclexta) for people with chronic lymphocytic leukemia (CLL) to include those whose cancer has progressed after previous treatment, regardless of whether their cancer cells have the deletion 17p gene alteration.

This NCI-funded Children’s Oncology Group trial tested the addition of nelarabine (Arranon) to standard treatment for children and young adults with T-cell acute lymphoblastic leukemia (T-ALL).

People diagnosed with hairy cell leukemia (HCL) may have an effective new treatment option, a type of drug called an immunotoxin. Read more about how this treatment, moxetumomab pasudotox, fared in a phase 3 clinical trial in patients with advanced HCL.

A new study has identified a possible strategy for improving the efficacy of a toxin-based cancer treatment, moxetumomab pasudotox, in some patients with acute lymphoblastic leukemia (ALL).

An NCI-funded study has found significant differences in the genetics of acute myeloid leukemia in younger and older patients. The findings could help guide the development of treatments tailored specifically for childhood AML.

On December 22, FDA approved an update to the label of nilotinib (Tasignia) that states that some patients with CML who are taking nilotinib and whose cancer has been in remission for an extended period can safely stop taking it.

Interim results from an ongoing clinical trial show that patients with relapsed or refractory chronic lymphocytic leukemia treated with rituximab plus venetoclax have longer progression-free survival compared with patients treated with chemotherapy.

In a unique clinical trial, a group of oncologists with experience treating acute promyelocytic leukemia are making themselves available around the clock to help clinicians at hospitals across the country treat their APL patients.

On November 9, the FDA approved dasatinib (Sprycel®) for the treatment of children with chronic myelogenous leukemia (CML) whose cancer cells express the Philadelphia chromosome and whose disease is in a relatively early stage, known as the chronic phase.

FDA has approved gemtuzumab ozogamicin (Mylotarg™) for adults with newly diagnosed CD33-positive AML and patients 2 years and older with CD33-positive AML who have experienced a relapse or whose disease has not responded to initial treatment.

FDA has approved inotuzumab (Besponsa®) for some adults with B-cell acute lymphoblastic leukemia (ALL). The approval covers patients with B-cell ALL whose disease has relapsed or is refractory to standard chemotherapy.

FDA has approved tisagenlecleucel (Kymriah™), a type of immunotherapy called CAR T-cell therapy, for some children and young adults with advanced acute lymphoblastic leukemia (ALL).

FDA has approved two new treatments for some adult patients with acute myeloid leukemia (AML): enasidenib (Idhifa®), which targets the IDH2 protein; and liposomal cytarabine-daunorubicin CPX-351 (Vyxeos®), a two-drug chemotherapy combination encapsulated in liposomes.

FDA changed its accelerated approval of blinatumomab (Blincyto) for some patients with acute lymphoblastic leukemia to a full approval and expanded the approved indications for its use.

The FDA has approved a new formulation of rituximab, Rituxan Hycela, that reduces treatment administration time for patients with several types of blood cancer.

The FDA has approved midostaurin for patients with newly diagnosed acute myeloid leukemia (AML) with mutations in the FLT3 gene. The approval also covers several rare conditions.

Results from a large phase III clinical trial suggest that a highly intensive preparatory regimen should be used for younger patients with acute myeloid leukemia or myelodysplastic syndromes preparing to undergo an allogeneic stem cell transplant.

Patients with previously treated acute lymphoblastic leukemia who received blinatumomab, which encourages the immune system to kill cancer cells, lived longer and experienced fewer side effects than patients given standard chemotherapy.

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High incidence of minor and micro breakpoints in Chronic Myeloid Leukaemia with additional cytogenetic abnormalities at diagnosis - the Western Australian series

Affiliations.

• 1 School of Medicine, University of Western Australia, Australia.
• 2 PathWest Laboratory Medicine, Western Australia, Australia.
• 3 Fiona Stanley Hospital, Western Australia, Australia.
• PMID: 36032422
• PMCID: PMC9411674
• DOI: 10.1016/j.lrr.2022.100344

Introduction and objective: Chronic Myeloid Leukaemia (CML) is defined by the presence of the Philadelphia chromosome, a balanced translocation between chromosomes 9 and 22 that results in the constitutively active tyrosine kinase, BCR-ABL1. Additional chromosomal abnormalities (ACAs) at diagnosis occur in 5-10% of CML patients, and are important for prognosis. They are classified as major or minor route. The purpose of our study was to determine the frequency and type of ACAs in 193 newly diagnosed CML patients, and to evaluate patient characteristics, treatment response, and survival.

Methods: Medical records, in conjunction with data from the PathWest cytogenetics and molecular laboratories, were analysed.

Results: ACAs were present in 14 (7.3%) of patients at diagnosis. Seven patients had major-route abnormalities, with additional chromosome 8 (+8) the most common. All patients were treated with tyrosine kinase inhibitors (TKIs). Three patients presented in blast crisis; two patients have died. Of note, there was a high incidence of the rare minor and micro BCR-ABL1 fusion transcripts.

Conclusions: Frequency of ACAs at diagnosis was similar to that of previous reports. These patients consist a higher-risk cohort, and require individualised treatment, with consideration of frontline and secondary TKIs, adjunct chemotherapy, novel agents, and allogeneic stem cell transplant.

Keywords: ACA, Additional chromosomal abnormalities; Additional chromosomal abnormalities; CML, Chronic myeloid leukaemia; Chronic Myeloid Leukaemia; Cytogenetics; Leukaemia; TKI, Tyrosine kinase inhibitor; Tyrosine kinase inhibitors.

Crown Copyright © 2022 Published by Elsevier Ltd.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Cumulative incidence of major molecular…

Cumulative incidence of major molecular response (MMR).

Kaplan-Meier analysis of overall survival.

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Current research into leukaemia

For the past 120 years, we’ve been making discoveries that have saved countless lives. But we have so much more to do. Our strategy sets out how we'll accelerate progress towards a better future.

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We’re tackling all types of leukaemia, from understanding the genetics of leukaemia cells and how this changes over time, to leading clinical trials of new treatments. Below are some examples of what our researchers are doing right now.

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Professor George Vassiliou, Cancer Research UK senior clinical fellow at the Cambridge Stem Cell Institute, University of Cambridge, and his team are identifying new treatment targets and translating their findings into new treatments for acute myeloid leukaemia (AML). In parallel, they have discovered that many people at risk of developing AML can be identified years in advance, and are developing ways to identify those at risk with the aim of preventing progression to AML in the future.

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Professor Katrin Ottersbach at the University of Edinburgh is looking into the biology of B-cell acute lymphoblastic leukaemia and how it develops in infants from pre-birth. This type of blood cancer is rare and affects children who are less than 1. She hopes this work will lead to the discovery of new early detection markers and targets for treatment for this type of cancer

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Professor Peter Hillmen in Leeds is leading a clinical trial testing a new treatment for chronic lymphocytic leukaemia (CLL), the most common type of blood cancer. The aim is to test if a new targeted drug works as well as the chemotherapy currently used to treat CLL, but with far fewer side effects. 

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At the Barts Cancer Institute in London, Dr Diu Nguyen is investigating a new therapeutic target in leukaemic stem cells, the cells that propagate acute myeloid leukaemia. This new target could allow the development of drugs that selectively kill cancerous stem cells without killing normal blood stem cells, leading to better leukaemia treatment. 

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Glutamine and leukemia research: progress and clinical prospects

• Open access
• Published: 31 August 2024
• Volume 15 , article number  391 , ( 2024 )

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• Zexin Wang 1 ,
• Miao Liu 1 &
• Qiang Yang 1  

Leukemia is an abnormal proliferation of white blood cells that occurs in bone marrow and expands through the blood. It arises from dysregulated differentiation, uncontrolled growth, and inhibition of apoptosis. Glutamine (GLN) is a "conditionally essential" amino acid that promotes growth and proliferation of leukemic cells. Recently, details about the role of GLN and its metabolism in the diagnosis and treatment of acute myeloid, chronic lymphocytic, and acute lymphoblastic leukemia have emerged. The uptake of GLN by leukemia cells and the dynamic changes of glutamine-related indexes in leukemia patients may be able to assist in determining whether the condition of leukemia is in a state of progression, remission or relapse. Utilizing the possible differences in GLN metabolism in different subtypes of leukemia may help to differentiate between different subtypes of leukemia, thus providing a basis for accurate diagnosis. Targeting GLN metabolism in leukemia requires simultaneous blockade of multiple metabolic pathways without interfering with the normal cellular and immune functions of the body to achieve effective leukemia therapy. The present review summarizes recent advances, possible applications, and clinical perspectives of GLN metabolism in leukemia. In particular, it focuses on the prospects of GLN metabolism in the diagnosis and treatment of acute myeloid leukemia. The review provides new directions and hints at potential roles for future clinical treatments and studies.

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1 Introduction

Leukemias are a group of aggressive hematologic malignancies (also known as blood cancers) involving clonal proliferation of immature myeloid progenitor cells in the bone marrow and peripheral blood. They are caused by genetic mutations in hematopoietic stem cells. Presently, the treatment of choice includes chemotherapy and allogeneic stem cell transplantation [ 1 ]. With the development of time and technology, immunotherapeutic approaches for various leukemias have shown great promise, such as CD33 or CLL-1-specific chimeric antigen receptor (CAR)-T cell therapy[ 2 , 3 ] and immune checkpoint inhibitor therapies such as TIM3, CD47, and anti-CD70 [ 4 , 5 , 6 ]. Regardless of therapy, relapse is common and shortens the survival of leukemia patients. Therefore, alternative treatment strategies are needed.

Growing evidence points to the critical role of amino acid metabolism on the diagnosis and treatment of leukemia. The metabolic pathways for GLN, arginine, isoleucine, tryptophan, cysteine, tyrosine, threonine, and L-serine play a crucial role in cancer. Moreover, amino acid metabolism is active in high-risk populations and the corresponding genes are associated with the immune microenvironment in acute myeloid leukemia (AML) patients [ 7 ]. Among the various amino acids, GLN metabolism seems to be an effective target against leukemia [ 8 ]. Leukemia cells have changes in the uptake and utilization of GLN as well as metabolic pathways. Through the dynamic changes of GLN-related indexes in patients can help to determine whether the leukemia is in progress, remission or relapse, and the differences in glutamine metabolism in different subtypes of leukemia can help to differentiate between subtypes of leukemia. Therefore, this review discusses the role of GLN metabolism in three common types of leukemia: AML, chronic lymphocytic leukemia (CLL), and acute lymphoblastic leukemia (ALL). Furthermore, it discusses the latest advances and developments in the field, as well as the therapeutic opportunities and challenges of GLN targeting.

2 Glutamine metabolism

GLN is a nonessential amino acid with two amino groups, the α-amino group and a readily hydrolysable side-chain amide group, with five carbons, a molecular weight of 146.15 kDa, and a chemical composition of C = 41.09%, H = 6.90%, O = 32.84%, and N = 19.17%. Classified as a neutral at physiological pH, it is the most abundant and versatile amino acid in the body (~ 0.6–0.8 mM) [ 9 ]. GLN is converted by glutaminase (GLS) to glutamate, which is then transformed to α-ketoglutarate (α-KG), an intermediate in the tricarboxylic acid (TCA) cycle and a core element in GLN metabolism [ 9 , 10 ]. Glutamate can be directly converted to α-KG in two ways. The first is via glutamate dehydrogenase (GLDH), which produces the potential autophagy inducer ammonium and NADH or NADPH as cofactors. The second is via a group of transaminases, including glutamate–oxaloacetate transaminase, glutamate-pyruvate transaminase, and phosphoserine aminotransferase. Glutamate serves as a metabolite for the growth and proliferation of cancer cells via the TCA cycle. Moreover, glutamate can be deaminated in a number of reactions, thus providing a source of nitrogen for nonessential amino acids, purines and pyrimidines [ 11 ]. At the same time, intracellular glutathione (GSH) derived from GLN effectively scavenges intracellular reactive oxygen species (ROS), mediating ferroptosis and redox homeostasis in cancer cells [ 8 ]. Notably, GLN promotes the activation of rapamycin complex 1 (mTORC1), which is associated with apoptosis and autophagy in cancer cells.

GLN is as important in hematologic tumors as one of the nutrients on which cancer cells depend for survival. Given the need of tumor cells for glucose (for anaerobic glycolysis), GLN deficiency has been associated with cell death [ 12 , 13 , 14 ]. In both healthy and diseased states, immune cells consume as much GLN as possible, and its deprivation holds promise as a new therapeutic tool.

3 Glutaminase

GLS is a key enzyme involved in GLN metabolism. It comprises renal glutaminase-1 (GLS-1) and hepatic glutaminase-2 (GLS-2). GLS-1 has two variable splice isoforms: glutaminase C and renal glutaminase. The TCA cycle yields metabolic intermediates that are involved in the biosynthesis of nucleotides, GSH, and other amino acids [ 15 ]. In addition, GLN can be converted to α-KG for oxidative phosphorylation to produce ATP. Elevated expression of GLS-1 is directly or indirectly associated with poor prognosis in stem cell, colorectal, and breast cancers [ 16 ].

The GLS-2 gene is located on chromosome 12q13 and contains 18 coding exons. GLS-2 is considered more of a tumor suppressor than GLS-1. GLS-2 has been shown to be a p53 target as it contains two possible p53 binding sites [ 17 ]. The tumor suppressor p53 activates GLS-2 expression, regulates intracellular ROS levels and reduced/oxidized GSH ratios, and removes intracellular ROS to protect cells from genomic damage and ROS-sensitive apoptosis [ 18 , 19 ]. TAp63, TAp73, and long-chain non-coding RNAs can also regulate GLS-2 [ 20 , 21 , 22 ]. Meanwhile, increased mitochondrial GLS expression enhances GLN catabolism by Myc oncogene inhibition of miR-23, which in turn targets GLS [ 23 ]. GLS inhibition decreases the production of GSH in AML cell lines, leading to increased mitochondrial ROS and apoptosis [ 8 , 24 ]. Thus. GLS-1 and GLS-2 may serve as diagnostic and therapeutic targets for certain cancers. Clinical studies should explore new chemotherapeutic combinations of GLS inhibitors in the treatment of leukemia.

4 Inhibitors of the GLN transporter limit tumor demand for GLN

Strong expression of alanine-serine-cysteine transporter protein 2 (ASCT2), a GLN transporter, helps meet the amino acid needs of tumors [ 25 ] (Fig.  1 ). However, ASCT2 has also anticancer properties [ 26 ], because its deletion can lead to apoptosis of leukemia cells [ 27 ]. Inhibition of ASCT2-mediated GLN uptake in human cells using a lead compound (V-9302) resulted in attenuation of cancer cell growth and proliferation, frequent cell death, and increased oxidative stress [ 28 ]. ASCT2 plays the same role in cell proliferation and apoptosis in several cancers [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. In a study of 25 patients with different clinically aggressive tumors (lung, breast, colon, or lymphoma), who underwent fluorine 18-(2S,4R)-4-fluoroglutamine positron emission tomography, all showed abnormal GLN metabolism [ 37 ]. Notably, ASCT2-mediated pharmacological inhibitors significantly reduced GLN uptake by triple-negative basal-like breast cancer cells, while having little effect on luminal breast cancer cells [ 38 ]. Taken together, this evidence implies that ASCT2 may serve as a potential target for antitumor drugs. ASCT2 inhibitors and the combination of ASCT2 inhibitors with other antitumor therapies may offer a promising antitumor strategy. However, more research is needed in this area of leukemia. Because GLN may be closely related to leukemogenesis and progression, it may directly or indirectly affect the diagnosis and treatment of leukemia.

Overview of glutamine metabolism in leukemia cells. The increased demand for glutamine by leukemia cells and simultaneous inhibition of the ASCT2 transporter, result in a declining hydrolysis of glutamine to glutamate. α-KG, α-ketoglutarate; ASCT2, alanine-serine-cysteine transporter protein 2; GLS, glutaminase; TCA, tricarboxylic acid. The Illustration was created in Figdraw

5 GLN metabolism in leukemia

Leukemia is a myeloid malignancy characterized by abnormal proliferation and differentiation of hematopoietic precursor cells. Cancer cells are highly dependent on GLN metabolism and availability [ 39 ]. GLN metabolism is centered in the mitochondria. Mitochondria play a crucial role in the maintenance of hematopoietic stem cells, whose malignant transformation ultimately leads to leukemic stem cells [ 40 ]. The first evidence of impaired mitochondrial metabolism in AML was the presence of mutations in the gene encoding isocitrate dehydrogenase (IDH) in AML patients [ 41 , 42 ].

Recent in vivo and in vitro studies have shown that GLN is restricted to the cancer cell environment [ 43 ]. Glutamine is used as an alternative fuel for the TCA cycle, with plasma concentrations of 0.6–0.8 mM, and is the most common amino acid in blood [ 9 , 10 ]. As in other cancers, plasma GLN concentrations in AML patients are quite low, 0.3 mM or less, suggesting that GLN is rapidly depleted in AML cells [ 10 , 44 , 45 ]. A study of 55 newly diagnosed AML patients and 45 healthy individuals also showed that GLN levels were much lower in the former than in the latter [ 46 ]. AML cells are completely dependent on exogenous GLN, and knockdown of high-affinity ASCT2 leads to apoptosis in AML cell lines and inhibits tumor progression in AML xenografts and primary AML mouse models [ 47 ] Indeed, ASCT2 plays pleiotropic roles in cellular metabolism and serves as a promising molecular target for the treatment of leukemia [ 27 ].

GLS is a rate-limiting factor for TCA activity in AML and is highly expressed in AML patients [ 48 ]. The initial step required for glucose-independent oxidative phosphorylation is the conversion of GLN to glutamate. Subsequently, glutamate provides the substrate for the synthesis of α-KG. IDH catalyzes the oxidative decarboxylation of isocitrate to α-KG. Mutations in IDH result in the conversion of α-KG to R2-hydroxyglutarate, which is detected in approximately 2% of adult AML patients [ 42 , 49 ] (Fig.  2 ). ATP and metabolic pathways localized to the mitochondria have been shown to play an important role in the progression of AML [ 50 ]. Elevated levels of 2-hydroxyglutarate, a metabolite associated with the TCA cycle, may promote tumorigenesis [ 51 ]. Meanwhile, the central nervous system is also involved in metabolic processes, posing a major challenge to the treatment of acute leukemia [ 52 ]. In addition, in studies on GLN metabolism, N6-methyladenosine (m 6 A) regulates GLN metabolism through modification of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), which directly or indirectly promotes AML cell development and self-renewal, and higher levels of IGF2BP2 expression correlate with a poor prognosis for AML [ 53 ].

Strategies for targeting glutamine metabolism in AML. l -asparaginase allows the hydrolysis of extracellular glutamine, impeding its synthesis and hydrolysis. Upon translocation to the cell, glutamine is transformed to glutamate by the two isoforms of glutaminase, GLS-1 and GLS-2. Glutamine is synthesized from glutamate and ammonia (NH 3 ) by glutamine synthetase. In this reaction, an ATP is consumed. The reverse reaction yields glutamate and ammonium ions (NH 4 + ). Almost all cells in the body contain glutamine and ammonium ions, and express both glutamine synthetase and GLS. The predominant expression of one or the other of these enzymes will determine whether tissues are more likely to produce or consume glutamine. α-KG, α-ketoglutarate; ASCT2, alanine-serine-cysteine transporter protein 2; GLS, glutaminase; GSH, glutathione; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species; TCA, tricarboxylic acid; XCT, cystine/glutamate transporter

Taken together, changes in glutamine utilization and metabolic pathways in leukemia cells are expected to be potential prognostic markers. For example, GLS is highly expressed in AML patients and IGF2BP2 is associated with prognosis in AML. By detecting dynamic changes in glutamine-related markers, it is possible to understand the progression, remission or relapse of leukemia and provide diagnostic value. Glutaminolysis inhibits the conversion of GLN to circulating TCA metabolites by regulating various enzymes, and GLS is the first step in the process. Therefore, targeting GLS to block GLN degradation is a promising therapeutic strategy. Targeting of the two GLS isoforms, GLS-1 and GLS-2, will provide new insights on the treatment of leukemia. Hereafter, we discuss the relationship between GLN and AML, CLL, and ALL.

6 Glutamine as a therapeutic strategy for leukemia

6.1 acute myeloid leukemia.

Reducing intracellular GLN levels in AML patients is one of the main strategies for AML treatment. The most important step in targeting GLN is the use of GLS to catalyze the deamination reaction of GLN to glutamate. Glutamate is further catabolized and metabolized to α-KG which feeds into the TCA cycle to provide energy. Therefore, glutaminase inhibitors are a popular antitumor strategy [ 54 ]. In particular, the renal-type GLS-1 form disrupts GLN-driven oxidative phosphorylation in AML cell lines, thereby preventing tumor growth and inducing apoptosis [ 55 ].

Blocking GLN metabolism with the GLS inhibitor CB-839 results in GSH depletion [ 56 , 57 ]. In AML, where GSH acts as an antioxidant, a decrease in GSH leads to the accumulation of mitochondrial ROS and subsequent apoptosis [ 58 , 59 ]. At the same time, the inhibitory effect of CB-839 makes AML cells more sensitive to adjuvants of the mitochondrial redox state, such as arsenic trioxide and hypertriglyceride [ 8 ]. Therefore, CB-839 applied together with the above adjuvants induces apoptosis in AML cells. In addition to inducing apoptosis in AML cells, CB-839 inhibits also the mTOR signaling pathway [ 54 ]. In AML cells, GLN condenses with cysteine and glycine to produce GSH, which maintains redox homeostasis, prevents ROS-induced damage, and provides a nitrogen source for DNA replication [ 55 , 60 ]. In addition, many AML gene mutations have been shown to be associated with a number of mutations. In addition, many AML gene mutants are specific for GLN metabolism. For example, the glutaminase inhibitor BPTES was able to target and inhibit the unique metabolic profile of primary AML cells with IDH mutations (i.e., glutamine addiction), which in turn slowed the growth of primary AML cells with mutant IDH [ 49 ]. The fact that there is a unique selective inhibitory effect of interfering with glutamine metabolism on AML cells with IDH mutations is demonstrated. Other than this, aberrant expression of the FMS-like tyrosine kinase 3 (FLT3) gene in AML also leads to disorders of glutamate metabolism [ 61 ]. Approximately 25–30% of AML cases show hyperactivation due to mutations in tandem duplications within genes (FLT3–ITD) or in the structural domain of tyrosine kinase (FLT3–TKD) [ 62 ]. The FLT3 inhibitor AC220 (also known as Quizartinib) decreases GLN uptake and GSH production in AML cells, while increasing sensitivity to oxidative stress [ 63 ]. In addition, GLN is also used as a parenteral nutrient to assist in the treatment of AML. In a randomized, double-blind, controlled study including 45 adult AML patients and 127 cycles of chemotherapy, GLN improved the clinical course of patients after bone marrow transplantation and parenteral nutrition [ 64 ]. If in AML, the degree of GLN dependence of AML cells with specific gene mutations (e.g. IDH mutations and FLT3 mutations) is investigated. It is possible to assist in the diagnosis of such subtypes of AML with specific gene mutations by detecting GLN-related metabolic markers.

At present, the specific quantitative indicators and the exact extent of GLN dependence in AML subtypes with specific genetic mutations need to be investigated in further studies. In general, however, this dependence may be manifested by an increased rate of cellular uptake and utilization of GLN, increased activity of enzymes involved in intracellular GLN metabolism, and a more critical role of the GLN pathway in maintaining cell survival, proliferation, and energy supply. In conclusion, GLN is essential for the treatment of leukemia and is an effective therapeutic strategy. It is also important in medical research as a nutrient to support cell growth and repair, and as a potential antitumor agent for the treatment of leukemia.

6.2 Chronic lymphocytic leukemia

The 13q deletion is the most common cytogenetic mutation in CLL. Bruton’s tyrosine kinase and B-cell lymphoma-2 inhibitors are widely used in the clinic for the treatment of CLL; however, CLL cells have developed resistance to these drugs. CB-839, a small-molecule GLS-1 inhibitor, decreases GLS-1 activity and inhibits CLL cell proliferation; however, the efficacy of CB-839 is limited in combination with conventional CLL drugs [ 65 ]. In addition, CLL lymphocytes in del11q-positive CLL cells exhibit altered glutamine metabolism [ 66 ]. Mitochondria in CLL have been reported to increase ROS production [ 67 ]. The role of GLN in preventing the overproduction of ROS underscores its importance in tumor growth and energy production [ 68 ].

6.3 Acute lymphoblastic leukemia

Acute lymphoblastic leukemia is a heterogeneous malignancy of immature B or T lymphoblastoid cells that is most prevalent in children [ 69 , 70 ]. l -asparaginase (ASNase) is the first-line therapy for childhood ALL [ 71 , 72 ], as well as adult ALL [ 73 ]. ASNase hydrolyzes GLN to produce glutamate and may be considered for patients with Notch1 ALL positivity [ 74 ]. The notch1 receptor is effective in the treatment of ALL. Notably, when GLN is secreted by adipocytes, its cytotoxicity towards ALL cells is blocked [ 75 ]. Therefore, targeting GLN and ASNase may also serve in the development of novel therapeutic agents [ 76 , 77 ]. In addition, GLN nutritional therapy during chemotherapy can effectively improve and enhance the systemic nutritional status and immunity of pediatric patients with ALL [ 78 ]. Notably, there are genomic differences in relapsed ALL during treatment [ 79 ]. Among these differences, reduced dependence on GLN is an important cause of drug resistance in leukemia cells [ 80 ].

Mitochondria are one of the major sources of ROS production. Redox dysfunction plays a crucial role in leukemogenesis in ALL, and inhibition of ROS production via NADPH oxidases is a novel therapeutic tool for the treatment of ALL [ 81 ]. Many enzymes neutralize ROS, including superoxide dismutase, catalase, glutathione peroxidase (GPX), thioredoxin, peroxiredoxin, and glutathione transferase [ 82 ]. In addition, activating mutations in NOTCH1 are common in T-cell ALL, and inhibition of NOTCH1 signaling suppresses and promotes autophagy during GLN catabolism [ 83 ]. GLN metabolism regulates the expression of mitochondrial uncoupling protein 2 (UCP2) in T-cell ALL cell lines, and UCP2 is required for T-cell ALL proliferation [ 84 ]. A link between UCP2 and ROS production has been demonstrated [ 85 ]. Therefore, promoting GSH production by blocking GLN metabolism and indirectly preventing ROS production is a novel therapeutic strategy for ALL.

7 GLN causes cellular ferroptosis in an indirect way

In clinical settings, radiotherapy remains the mainstay treatment for leukemia, although GLN-targeting agents (e.g., CB-839) have been developed to indirectly induce ROS production [ 8 ]. It is well known that ROS production and lipid peroxidation is a key feature and an important step in iron death, and the generation of ROS promotes lipid peroxidation, which in turn triggers iron death. However, the mechanism of iron death involves a variety of factors, including antioxidant system factors, such as GSH and GPX4, which are important mechanisms of iron death [ 86 , 87 ]; iron metabolism factors, such as Fe 2+ which promotes the production of ROS through the Fenton reaction and so on, which in turn promotes lipid peroxidation [ 88 ]; lipid metabolism-related factors, such as lipoxygenase enzymes (LOXs), which can directly oxidize unsaturated fatty acids on biological membranes (PUFAs) and PUFA-containing lipids on biological membranes, which may induce iron death [ 87 ]; signaling pathway factors, such as cystathionine-glutamate transporter receptor (system Xc -), p53, and other pathways can regulate iron death. The mechanism underlying the role of GLN in leukemia remains unclear, and its use in clinical practice is relatively rare. Notably, p53-dependent activation of GLS-2 expression correlates with ROS, while elevated ROS levels lead to p53 stabilization and activation [ 89 ]. Sawako et al. demonstrated that GLS-2 reduces cellular sensitivity to ROS-related apoptosis [ 19 ]. Increased mitochondrial production of ROS and lipid peroxidation, along with decreased expression of GSH and GPX4, lead to ferroptosis [ 90 , 91 ]. The accumulation of intracellular iron during ferroptosis is important in leukemic cells. GLN metabolism enhances ROS production in the TCA cycle [ 92 , 93 , 94 ]. GLN catabolism inhibits intracellular GSH depletion and subsequent ROS generation [ 49 , 95 ], as well as affecting the TCA cycle [ 96 ]. The accumulation of lipid ROS can lead to ferroptosis [ 96 ]. Notably, GLS-2 is present on the cell surface of human neutrophils [ 97 ], which promotes lipid ROS production and enhances ferroptosis by catalyzing the generation of α-KG from glutamate [ 98 , 99 ]. GLN increases α-KG levels and can activate amino acid sensor kinases, leading to formation of mTORC1 [ 100 , 101 ], which then regulates ferroptosis sensitivity [ 102 , 103 ]. In conclusion, increasing ROS levels through GLN metabolism promotes ferroptosis by blocking GSH synthesis (Fig.  3 ), which may provide new therapeutic guidelines for ferroptosis-based clinical treatment.

Glutamine induces ferroptosis. α-KG, α-ketoglutarate; ASCT2, alanine-serine-cysteine transporter protein 2; GLS, glutaminase; GPX4, glutathione peroxidase 4; GSH, glutathione; OXPHOS, oxidative phosphorylation; PLs, phospholipids; PUFA, polyunsaturated fatty acids; ROS, reactive oxygen species; TCA, tricarboxylic acid; XCT, cystine/glutamate transporter

8 Discussion

GLN and its metabolites have significant antileukemic effects. Because of the close association between GLN and leukemia prognosis, we have summarized the latest developments on GLN and leukemia-related drugs or other studies by publication date (in no particular order), category, and content (Table  1 ).

There are multiple pathways involving GLN in leukemia, along with multiple factors that regulate and interfere with each pathway. GLN metabolic pathway: Supplies carbon for TCA cycle intermediates and nitrogen for nucleotide and amino acid biosynthesis, and plays an important role in hematopoietic tumors and hematologic neoplasms [ 116 ]; Bypass pathway: when leukemia cells are deprived of Gln, the serine pathway upregulates the key serine enzymes phosphoglycerate dehydrogenase (PHGDH) and phosphoribosyltransferase (PSAT), leading to an increased demand for serine and exacerbation of serine dependence in leukemia cells [ 117 ]; Lipid-related metabolism: AML cells are dependent on OXPHOS [ 118 , 119 , 120 ], AML cells obtain free fatty acids from bone marrow adipocytes and utilize fatty acid oxidation (FAO) and OXPHOS to maintain AML cell survival and growth [ 121 , 122 , 123 ]. However, OXPHOS-deficient cells accelerate the utilization of GLN, and GLN depletion promotes the accumulation of ROS [ 124 ]. We also note that targeting GLN and GLN metabolism (or parts of it) may have a limited impact on leukemia therapy. For example, ASCT2 is not the sole transporter for GLN [ 125 ]. This suggests that GLN influences the development and progression of leukemia. Therefore, future studies related to GLN should focus on the inhibition of multiple metabolic pathways for the effective treatment of leukemia.

Research on human leukemia therapy and GLN continues. The body's immune cells are also the focus of our interference with GLN, both in terms of the dependence of cancer cells on GLN and as a component of the TCA cycle. For example, immune cells use GLN to grow rapidly and gain immunity [ 126 ]. Reprogrammed GLN metabolism plays an important role in the antitumor immune response of immune cells, such as T cells, B cells, macrophages, and natural killer cells [ 127 ]. Parenteral GLN supplements may be relevant in the anti-tumor immune response, as they enhance neutrophil phagocytosis and maintain the nutritional status [ 128 ]. Inhibition of GLN metabolism can lead to immune escape for cancer cells, as observed with the GLN inhibitor V-9302 in human breast cancer cells [ 129 ]. Therefore, further experiments should be conducted to determine whether GLN inhibitors and related drugs disrupt the anticancer effects of immune cells in the bone marrow microenvironment during diagnosis and treatment. Targeting GLN metabolism in cancer cells without interfering with the immune response is a major challenge for future research.

9 Conclusion

Existing evidence points to the attractiveness of GLN as a new target for the treatment of leukemia. This strategy is already exemplified by CB-839 and V-9302, but includes also mTOR signaling and apoptosis in AML cells. Expression of an abnormal gene (FLT3) can cause GLN metabolic disorders. In addition, GLN plays an important role in CLL and ALL. The key enzyme in GLN metabolism is the GLS-2 isoform, which acts as a tumor suppressor. It activates and promotes hepatic glutamine catabolism and triggers the activation of mTORC1, a signal that also controls ferroptosis.

Inhibitors of GLN metabolism have also some limitations in the treatment of leukemia. First, a clear framework for clinical care has not been established, and there is a lack of additional empirical support for the use of GLN inhibitors to improve the prognosis of leukemia. More experimental studies are needed to provide better empirical data to improve the prognostic gap in GLN treatment of leukemia. Second, numerous studies have been conducted on AML, while relatively few have considered other types of leukemia (including, but not limited to, leukemia with rare genotypes and phenotypes). Such studies could determine whether the mechanism of action is the same in AML as in other types of leukemia.

In conclusion, available studies suggest that GLN is an attractive new strategy for the treatment of leukemia.

10 Future directions

The study of GLN in leukemia is in its preliminary stages, and its mechanism of action and clinical applications need further investigation. Future studies can focus on the following aspects: (1) the regulatory effect of GLN on various functional molecules in leukemia cells, (2) the regulatory mechanism of GLN on the relevant functional molecules in leukemia cells, (3) the application of GLN in leukemia treatment, (4) the effects of GLN on leukemia cell functions, such as cellular energy supply mechanisms, essential molecules, intracellular redox homeostasis mechanisms, and related signaling pathways for survival and proliferation, and (5) the effect of GLN on the prognosis of leukemia patients. The accrued knowledge will provide a new perspective for the effective clinical treatment of different types of leukemia.

Data availability

No datasets were generated or analysed during the current study.

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Wang, Z., Liu, M. & Yang, Q. Glutamine and leukemia research: progress and clinical prospects. Discov Onc 15 , 391 (2024). https://doi.org/10.1007/s12672-024-01245-0

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Late presentation of chronic myeloid leukaemia patients in a low-income country: the prognostic implications and impact on treatment outcome

• Elisha A. Nelson 1 ,
• Ibrahim O. Ahmed 1 ,
• Rahman A. Bolarinwa 1 , 2 ,
• Babatunde A. Adeagbo 3 ,
• Adebanjo J. Adegbola 3 ,
• Lateef Salawu 1 , 2 ,
• Oluseye O. Bolaji 3 &
• Muheez A. Durosinmi 1 , 2  

BMC Research Notes volume  17 , Article number:  245 ( 2024 ) Cite this article

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In Nigeria, since 2002, Imatinib mesylate (glivec ® ) has been available freely to chronic myeloid leukaemia (CML) patients but only at a tertiary health care centre in the southwestern part of the country. Despite this, it is not readily accessible to many patients due to the distance and other challenges including low socioeconomic status and political problems, preventing timely access to specialist care. This study evaluated the effect of the baseline characteristics on the prognostic implication and treatment outcome of CML patients in Nigeria.

This study retrospectively evaluated the baseline characteristics, clinical presentations and treatment outcomes of 889 CML patients over 18 years (2002–2020). Of these, 576 (65%) patients had complete information with up-to-date BCR::ABL1 records. These 576 patients were categorized based on their responses to Imatinib therapy into three groups viz.; Optimal response (OR) defined as BCR::ABL1 ratio of < 0.1% or major molecular remission (≥ 3-log reduction of BCR::ABL1 mRNA or BCR::ABL1 ratio of < 0.1% on the International Scale), Suboptimal response (SR) with BCR::ABL ratio of 0.1–1%, and Treatment failure (TF) when MMR has not been achieved at 12 months. The variables were analyzed using descriptive and inferential statistics and a p-value < 0.05 was considered statistically significant.

The result revealed a median age of 37 years at diagnosis with a male-to-female ratio of 1.5:1. The majority (96.8%) of the patients presented with one or more symptoms at diagnosis with a mean symptom duration of 12 ± 10.6 months. The mean Sokal and EUTOS scores were 1.3 ± 0.8 and 73.90 ± 49.09 respectively. About half of the patients presented with high-risk Sokal (49%) and EUTOS (47%) scores. Interestingly, both the Sokal ( r  = 0.733, p  = 0.011) and EUTOS ( r  = 0.102, p  = 0.003) scores correlated positively and significantly with the duration of symptoms at presentation. Based on response categorization, 40.3% had OR while 27.1% and 32.6% had SR and TF respectively.

This study observed a low optimal response rate of 40.3% and treatment failure rate of 32.6% in our CML cohort while on first-line Imatinib therapy. This treatment response is strongly attributable to the long duration of symptoms of 12 months or more and high Sokal and EUTOS scores at presentation. We advocate prompt and improved access to specialist care with optimization of tyrosine kinase inhibitor therapy in Nigeria.

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Chronic myeloid leukaemia (CML) is a clonal, acquired genetic disorder of haemopoietic stem cells commonly defined by the presence of the Philadelphia chromosome (Ph+), detected in about 95% of patients [ 1 ]. The Ph + arises from the reciprocal translocation of genetic material between chromosomes 9 and 22. The resultant BCR::ABL1 oncoprotein is a constitutively active tyrosine kinase that activates numerous signal transduction pathways, leading to uncontrolled cell proliferation and reduced apoptosis [ 1 , 2 ]. In the United States, the age-adjusted incidence is 1–2 cases per 100,000, accounting for about 15% of newly diagnosed cases of leukaemia in adults [ 2 ].

The natural history of CML is that of a triphasic disease, comprising the chronic phase (CP), accelerated phase (AP) and the final blastic phase (BP) [ 1 , 2 ]. Most patients present during the chronic phase, and the transition from CP to more advanced stages (AP and BP) is believed to result from genomic instability [ 3 ]. Some patients are diagnosed asymptomatically during routine medical evaluation but may present with clinical features related to anaemia, weight loss, abdominal swelling/discomfort or other complications related to advanced disease [ 2 ].

The stage at presentation and the presenting clinical features may significantly affect the overall outcome of treatment. Thus, the prognostic score at presentation needs to be evaluated and the Sokal score has shown to be very useful in pre-determining patients’ response to imatinib treatment [ 4 , 5 ].

Treatment of CML with tyrosine kinase inhibitor (TKI) has been reported to induce a good response with durable remission and prolonged survival [ 6 , 7 , 8 ]. At 12 months of treatment with TKI, the European Leukaemia Net (ELN) defines optimal treatment response as being able to achieve a BCR::ABL1 ratio of < 0.1% (major molecular remission, MMR) and/or progressive increasing molecular remission after 12 months. The suboptimal response is defined by a BCR::ABL1 ratio of 0.1–1% at 12 months of commencement of TKI while treatment failure is defined by non-achievement of MMR (BCR::ABL1 ratio > 1%) at 12 months of commencement of TKI, or thereafter a loss of MMR or presence of clonal disease progression [ 9 ].

In Nigeria, most CML patients are treated in a referral tertiary health care centre where imatinib mesylate (Glivec ® ) is given to CML patients free via the Glivec International Patient Assistance Program (GIPAP), however, many of these patients present late before they can have access to Glivec ® and this invariably affects the overall response to treatment and treatment outcome. It is on this premise that we evaluated the baseline characteristics of our CML patients and the effect on their treatment response.

The study retrospectively evaluated the baseline characteristics, clinical presentation, and response to imatinib treatment of CML patients managed at a referral centre between the years 2002 and 2020. After ethical approval, 889 medical records were reviewed to extract the demographic and baseline information (age, sex distribution, symptoms and duration of symptoms, platelet count, blast cell count, spleen size, and the phase at presentation) of the patients at diagnosis. BCR::ABL1 transcript quantification was performed using the Reverse Transcriptase Quantitative Polymerase Chain Reaction (RT-qPCR-TaqMan Chemistry) method. In contrast, the transcript variant was performed using the Seeplex Leukaemia BCR::ABL1 transcript kit (Seegene, Seoul, Korea). In summary, the quantification steps involved include RNA extraction from whole blood/buffy coat using the Zymo-Research ® extraction kit followed by RNA transcription to produce cDNA and finally quantitative PCR assay (Agilent Stratagene –Mx3005P by Agilent Technologies, USA). Both transcript quantification and variant assay are mandatory at diagnosis, and quantification is recommended every 3–6 months for monitoring. The patients were categorized into various prognostic risk categories using the Sokal and EUTOS scores. The Sokal score was determined using the age, spleen size, platelet count and blast count and was calculated using the formula: - Sokal score = Exp [0.0116 × (age in years − 43.4) + 0.0345 × (spleen size − 7.51) + 0.188 9 ([platelet count ⁄ 700]2–0.563) + 0.0887 × (blast cell counts − 2.10)], where Exp is the exponential function. The patients were categorized into the three risk groups based on their Sokal score as proposed by Sokal et al. Low-risk (Sokal score of less than 0.8), intermediate-risk (Sokal score between 0.8 and 1.2), and high-risk (Sokal score greater than 1.2) [ 10 ]. The European Treatment and Outcome Study (EUTOS) risk score for CML uses the spleen size (cm) and the peripheral basophil percentage and was calculated using the formula: (7 x basophil [%]) + (4 x spleen [cm]). Two risk groups were identified as proposed by EUTOS and used to categorize the patients into low-risk (score of less than 87) and high-risk (score of greater than or equal to 87) [ 11 ]. Using the European Leukaemia Network (ELN) and the National comprehensive cancer network (NCCN) criteria, 576 patients with regular clinic visit and at least 2 BCR::ABL1 results for at a minimum of one year) were subsequently categorized into 3 groups; optimal responders, suboptimal responders, and the treatment failure groups based on their BCR::ABL1 results. Optimal response at 1 year was defined as a BCR::ABL1 ratio of < 0.1% or the achievement of MMR (≥ 3-log reduction of BCR::ABL1 mRNA or BCR::ABL1 ratio of < 0.1% on the International Scale)while suboptimal response was defined as a BCR::ABL1 ratio of 0.1-1%. Treatment failure was defined as a BCR::ABL1 ratio of > 1% [ 12 , 13 ]. Statistical analysis was done using IBM SPSS version 23(SPSS, Chicago, IL, http://www.spss.com ). Variables were presented as mean, median, range, and percentages. Pearson’s correlation was calculated to test the correlation between the duration of symptoms at diagnosis and the risk stratification score.

Table  1 shows the baseline characteristics of the 889 cases reviewed. The median age at diagnosis was 37 years, range (6-80years). The male-to-female ratio was 1.5:1. Twenty-eight (3.2%) patients were asymptomatic at diagnosis while 861 (96.8%) presented with one or more symptoms. The commonest symptoms were those related to splenomegaly. The mean duration of symptom(s) at presentation was 12 ± 10.6 months, range (0–96). The majority of the patients (86%) were diagnosed in the chronic phase of the disease while 11% and 3% presented in accelerated and blastic phases respectively. The mean Sokal score was 1.3 ± 0.8 with almost half (49%) presenting with a high score, while 33% and 18% presented with intermediate and low scores respectively. Similarly, the European Treatment Outcome Study (EUTOS) score was used for the risk stratification of the patients and a mean score of 73.90 ± 49.09 was observed. About half of the patients (47%) presented with a score of ≥ 87 and were categorized as high risk, while the remaining 53% had scores less than 87 and were classified as low risk.

Table  2 shows the symptoms at presentation. Twenty-eight (3.2%) cases were asymptomatic and were diagnosed on routine medical screening while 861 (96.8%) presented with one or more symptoms at diagnosis. The commonest symptoms were those related to splenomegaly (abdominal swelling/discomfort/pain, and easy satiety).

Table  3 shows the relationship between the duration of symptoms and the risk stratification scores (Sokal and EUTOS). The duration of symptoms had a statistically significant and positive correlation with both Sokal ( r  = 0.733, p-value = 0.011) and EUTO ( r  = 0.102, p-value = 0.003) scores at diagnosis. The corresponding Scatter plots between the duration of symptoms (months) and baseline Sokal and EUTOS scores at presentation are depicted in Figs.  1 and 2 below.

Scatter plots showing the relationship between the duration of symptoms (months) and baseline Sokal scores. N  = 889

Scatter plots showing the relationship between the duration of symptoms (months) and baseline EUTOS scores. N  = 889

Figure  3 shows the categorization and proportion of 576 CML patients with Optimal response (OR), Suboptimal response (SR), and Treatment failure (TF). Of the 576 patients, 232 (40.3%) belong to the OR category while 156 (27.1%) and 188(32.6%) were categorized as SR and TF respectively.

Categorization and Proportion of 576 CML patients with Optimal response (OR), Suboptimal response (SR), and Treatment failure (TF)

This study evaluated the characteristics of CML patients at a referral center from a low- and middle-income country (LMIC) where CML patients received free imatinib via the Glivec International Patient Assistance Program (GIPAP) now the Max Solution (MAS), fronted by Novartis pharmaceutical and the Max Foundation. A review of the medical records of 889 CML patients revealed a median age of diagnosis of 37 years. This result is similar to other studies where the median age at diagnosis among CML patients of African descent was not more than 40 years [ 14 , 15 ]. This value is lower than what was obtained from studies from the Western world where CML is a disease of older age [ 16 , 17 , 18 ]. The lower age incidence pattern of CML patients in this study is believed to be due to the age distribution of the African population rather than any other inherent biological characteristics [ 11 ]. The Male to Female ratio of 1.5:1 reported from this study is similar to the ratio reported from similar studies on CML in other parts of the world [ 15 , 16 , 17 , 18 ]. The male predominance in the incidence of CML has shown in this study is more likely to result from the difference in risk than in latency because it seems males have more target cells and are at risk of developing CML than females [ 18 ].

The mean duration of symptoms at presentation in this study was 12 ± 10.6 months. A similar longer mean duration of 18 months at diagnosis was reported by Koffi et al. among CML patients in Cote d’Ivoire [ 15 ]. The long duration of symptoms before diagnosis reported in our cohort is incomparable to what has been reported from centres in developed countries where the majority of patients are diagnosed asymptomatically during routine medical screening. This has been attributed to the availability of specialized healthcare that is accessible to patients [ 19 , 20 ]. The reason for this late presentation of our CML cohort as reported is probably due to ignorance and poor healthcare-seeking habits by the patients [ 21 ]. In underdeveloped and developing nations, people usually attribute their sickness to a spiritual attack that can only be cured through divine interventions thereby resorting to prayers or consulting the traditional healers before going to the hospital. Moreover, access to specialist care where prompt and accurate diagnosis of CML would be made may be a challenge and this is unconnected to difficult access to a tertiary health care facility, lack of robust health insurance scheme, poverty and low socioeconomic level, recurrent civil unrest, political crisis and high level of illiteracy among the populace [ 22 ].

Reports have shown that in developed countries, up to 50% of CML patients were diagnosed at the asymptomatic stage during routine medical checkups or investigations for other illnesses [ 2 , 19 ]. Conversely, in this study, only 3.2% of the patients were diagnosed asymptomatically. A low proportion of asymptomatic presentation of 3.9% was also reported by Bhatti et al. [ 23 ] in Pakistan which is also a developing country like Nigeria where the accessibility to timely specialized medical care is also limited, and medical checkups are not routinely done until there are obvious clinical signs of disease.

This study showed a mean Sokal score of 1.3 ± 0.8 at presentation, with almost half (49%) presenting with high-risk scores. This finding is similar to what was obtained from an earlier study on the survival of CML in Nigeria where the majority (64%) of the patients were diagnosed with intermediate, and high-risk Sokal scores [ 24 ]. Similarly, in Cote d’Ivoire, Koffi et al. [ 15 ] reported a high Sokal score in 39% of the CML patients. In contrast, Hoffman et al. [ 17 ] and Lee et al. [ 5 ] reported a greater proportion of CML patients that presented with lower Sokal scores in Europe and the United States respectively. Further risk categorization of the BCR::ABL1 positive CML patients was done based on the European Treatment and Outcome Study Score (EUTOS) score [ 13 ]. The EUTOS score, a more recent risk stratification score was described by Hasford et al. 2011 to predict complete cytogenetic response and subsequently progression free survival in patients with CML on imatinib. Two risk groups were identified as proposed by EUTOS and used to categorize the patients into low-risk (score of less than 87) and high-risk (score of greater than or equal to 87) [ 13 ]. This index study revealed that a sizeable number (47%) of patients presented with high-risk scores. This contradicts the findings from a study on the risk classification of 618 CML patients in Southern India using the EUTOS risk score. Findings from the latter study categorized 64% of the patients into low risk and 35.9% into high risk [ 25 ]. It is important to state that since India and Nigeria have a similar socioeconomic characteristic, [ 26 ] this disparity may not be unconnected to the fact that all their patients were enrolled in the chronic phase of CML. However, access to imatinib and other TKIs remains a challenge in Nigeria, it is made available freely only at one centre via the Glivec International Patient Assistance Program (GIPAP), now the Max Solution (MAS), fronted by Novartis pharmaceutical company and the Max Foundation, it will be important to compare this with the situation in India.

The factors responsible for the high proportion of patients presenting with high-risk prognostic scores compared with the Caucasians, cannot be far-fetched. It is probably connected to socioeconomic factors such as poverty, poor access to health care, poor health-seeking behaviours, paucity of specialist physicians, and scarcity of specialized health care. All these factors delay the presentation to the hospital and therefore delay the diagnosis.

As seen in this study, there was a statistically significant positive correlation between the Sokal and EUTOS scores and the duration of symptoms at presentation). Although, a study done by Usman et al. [ 4 ] revealed that variables such as age, and disease duration at the time of starting imatinib did not show any significant influence on response to imatinib, however, long duration of symptoms before the commencement of treatment in CML patients have been said to predict poor prognosis [ 27 , 28 ].

Though the Sokal score was developed in the pre-imatinib era, it still retains prognostic significance in imatinib-treated patients [ 4 ]. Thompson et al. [ 19 ] reported a high Sokal score as a predictor of increased relapse while Jabbour et al. [ 29 ] reported a better response rate in patients with a low baseline Sokal score. Moreover, a recent study in Nigeria also highlighted the importance of the Sokal score in imatinib-treated CML patients, Sokal score was identified as a predictor of imatinib-induced thyroid dysfunction [ 30 ].

Furthermore, when we evaluated the treatment outcome of the patients using the European leukaemia Network (ELN) criteria, 40.3% of the patients had an optimal response (OR), while 27.1% and 32.6% had suboptimal and treatment failure respectively. The 40.3% of optimal responders reported in this study is lower when compared with what was reported by Palandri et al. [ 6 ], in Italy, Preetesh et al. [ 7 ] in the United States, and Jabbour et al. [ 8 ] in the IRIS study. This lower overall response rate is related to multiple factors including late diagnosis, delayed access to TKIs, and poor adherence rate [ 31 ]. Patients with suboptimal and treatment failure are managed following the NCCN and ELN guidelines. Their recommendations include; evaluation of the patient’s compliance and the possibility of drug interaction, and mutational analysis. Physicians can consider increasing the dose of imatinib to a maximum dose of 800 mg or switching to alternate TKI. In addition to the earlier mentioned, allogeneic stem cell transplantation (ASCT) is recommended for patients with treatment failure [ 12 , 13 ]. Though second and third-line TKIs are available free courtesy of MAS but to a limited number of patients in Nigeria, management of patients with suboptimal and treatment failure in Nigeria is a herculean task. This is mainly due to the limited access to facilities for mutational analysis which is often unaffordable by most patients and the unavailability of facilities for ASCT. Undoubtedly, late presentation as a result of poor socioeconomic status is a major factor responsible for the poor response of patients to imatinib in Nigeria.

This study reported a low optimal response rate of 40.3% and a high treatment failure rate of 32.6% in Nigerian CML patients while on first-line Imatinib therapy. This observation is strongly attributable to the long duration of symptoms of ≥ 12 months before diagnosis and a resultant high risk categorisation score at presentation. Timely, accessible and affordable specialized care is strongly advocated to reverse the trend.

Data availability

The data sets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We like to appreciate the management of the Obafemi Awolowo University and Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria for providing the enabling environment for research.

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Elisha A. Nelson, Ibrahim O. Ahmed, Rahman A. Bolarinwa, Lateef Salawu & Muheez A. Durosinmi

Department of Haematology and Immunology, Obafemi Awolowo University, Ile-Ife, Nigeria

Rahman A. Bolarinwa, Lateef Salawu & Muheez A. Durosinmi

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NEA, BRA, SL and DMA contributed to conception and design of the study. NEA, AIO, BRA, ABA and AAJ obtained the data, NEA, AIO, BRA, AAJ, ABA, SL, BOO and DMA analysed and interpreted the data. NEA, AIO, BRA, ABA, AAJ, SL, BOO and DMA drafted the original manuscript. NEA AIO, BRA, ABA, AAJ, SL, BOO and DMA critically revised the manuscript. All authors read and approved the final manuscript.

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Nelson, E.A., Ahmed, I.O., Bolarinwa, R.A. et al. Late presentation of chronic myeloid leukaemia patients in a low-income country: the prognostic implications and impact on treatment outcome. BMC Res Notes 17 , 245 (2024). https://doi.org/10.1186/s13104-024-06910-9

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• Case report
• Open access
• Published: 04 September 2024

Acute lymphoblastic leukemia with nephrogenic diabetes insipidus as the first symptom: a case report

• Ning Qu 1 &
• Hongtao Zhu 1  

Journal of Medical Case Reports volume  18 , Article number:  421 ( 2024 ) Cite this article

Metrics details

Acute lymphoblastic leukemia is the most common pediatric malignancy, characterized by fever, anemia, hemorrhage, and symptoms brought on by blasts infiltrating organs.

Case presentation

This is a case report of a 9-year-old Asian patient with acute lymphoblastic leukemia who presented with polyuria alone as a presenting feature without any other clinical manifestation; primary renal disease or inherited metabolic disease was highly suspected. However, the water deprivation test and water deprivation pressurization test suggested nephrogenic diabetes insipidus, and the renal biopsy displayed diffuse lymphocytic infiltration in the renal interstitium. Bone marrow aspiration was performed immediately, and a comprehensive diagnosis of B-lymphoblastic leukemia was finally made.

Conclusions

Renal infiltration with leukemic blasts mostly remains asymptomatic, but our case suggests that it can present with nephrogenic diabetes insipidus. This case fully demonstrates that the presentation of extramedullary infiltration in acute lymphoblastic leukemia is varied. When the patient has renal diabetes insipidus as the first symptom, the possibility of hematological tumor infiltration should be considered when finding the cause, and timely bone marrow cytology should be performed.

Peer Review reports

Introduction

Leukemias are a group of life-threatening blood and bone marrow malignancies, while blasts have a characteristic ability to infiltrate and proliferate into various tissues and organs of the body. However, organ infiltration by blasts is associated with poor prognosis in leukemia [ 1 ]. The main localizations of extramedullary involvement are the central nervous system (CNS) and the testis [ 2 ]. The incidence of blasts directly infiltrating the kidney is high (up to 50%), but it is rare to develop obvious clinical symptoms [ 3 ]. Leukemia-related kidney damage can cause proteinuria, hematuria or even gross hematuria, hypertension, renal insufficiency, acute tubulointerstitial nephritis, renal tubular acidosis, acute uric acid nephropathy, low back pain, and acute tumor lysis syndrome [ 4 , 5 , 6 , 7 ]. Here, we report a case of ALL initially presenting with nephrogenic diabetes insipidus.

This case report involves a 9-year-old Asian boy who was admitted to our hospital with polyuria, vomiting, and generalized malaise for 3 months. He had no obvious medical history, including kidney or blood diseases. He also had no special family history, social history, intravenous drug history, or travel history. Three months before coming to our hospital, the child had experienced an increase in urination for no apparent reason. In the beginning, the child had a urine output of about 9.7 ml/kg/hour. He visited a local hospital and underwent some relevant examinations. Complete hemogram was normal except for mild anemia; serum potassium was 1.64 mmol/L, serum chlorine was 110 mmol/L, and other electrolytes were normal. Serum lactate dehydrogenase (LDH) was 155 U/L. Ultrasound examination showed no hepatosplenomegaly or lymphadenopathy but suggested bilateral renal enlargement with diffuse lesions (right kidney 9.2 cm × 4.9 cm × 3.7 cm, left kidney 9.4 cm × 5.2 cm × 3.9 cm). The local hospital made the following diagnoses: severe hypokalemia, diabetes insipidus, and renal tubular acidosis. The patient received treatments such as correcting acidosis, supplementing potassium, protecting the kidney, and protecting gastric mucosa. The patient was treated in the local hospital for 1 week, but the child’s polyuria still did not improve, and his urine output was still 9 ml/kg/hour, so he was then transferred to our hospital for further treatment. When he came to our hospital, his body temperature was 36.5 ℃, pulse was 78 beats per minute, respiratory rate was 20 breaths per minute, blood pressure was 128/76 mmHg, weight was 30 kg, height was 144 cm, muscle strength was 4 grade in the whole-body examination with no lymphadenopathy, and no abnormalities were found in the nervous system and other systems during the examination. Laboratory tests proved no significant abnormalities in complete blood counts, severe hypokalemia, metabolic acidosis, and renal tubular dysfunction. Critical laboratory findings are presented in Table  1 . Head + whole-spine magnetic resonance imaging (MRI) showed the following results: (1) no obvious abnormality in the head, cervical spine, thoracic spine, or lumbar spine; (2) renal volume was markedly elevated; (3) pituitary gland without suggestive lesion. Water deprivation test and water deprivation pressurization test (Table  2 ) excluded central diabetes insipidus. In summary, the primary diagnoses were nephrogenic diabetes insipidus, renal tubular acidosis, and severe hypokalemia. The following treatments were then given immediately: intravenous drip and oral potassium chloride supplements (up to 500 mg/kg/hour); hydrochlorothiazide 3 mg/(kg·day) combined with indomethacin 1 mg/(kg·day); oral desmopressin 0.4 mg (time, q8h); intravenous infusion of methylprednisolone 1 mg/(kg·day) to improve renal interstitial lesions. We initially believed it to be primary renal disease because the child only had bilateral renal enlargement and nephrogenic diabetes insipidus, therefore the child underwent a renal biopsy. After 1 month of treatment, the electrolyte level of the child was stable and the limb muscle strength was improved. Therefore, the child was discharged from hospital awaiting the results of renal biopsy and fully penetrant genetic testing. After his discharge, the following protocol for treatment was advised: potassium citrate extended-release tablets to supplement potassium, a bailing capsule to protect the kidney, and prednisone to improve kidney function. Prednisone dosage was 15 mg/day, taken in the morning. After 15 days of oral administration, the patient’s renal pathological results returned as follows: (1) diffuse lymphoid cell infiltration in the renal interstitium, which we considered to be derived from the lymphatic and hematopoietic system tumors; (2) mild-to-moderate renal tubular atrophy and interstitial fibrosis (Fig.  1 ); (3) sections of the kidney immunofluorescently stained (Table  3 ). Whole-exome sequencing suggested SCN4A gene mutation: hypokalemic periodic paralysis type 2 (OMIM: 613345) (Fig.  2 ). He was immediately notified by phone to follow up in the hospital and stop taking the prednisone. The family members of this child were contacted to inform them about the examination results and the need for hospitalization again. At that time, the child had polyuria again, and the urine volume was about 5–7 L. He was brought to our hospital again. We performed bone marrow aspiration immediately. Bone marrow morphology demonstrated that primitive lymphocytes + immature lymphocytes accounted for 35.5%. Bone marrow cytological staining results were as follows: myeloperoxidase (MPO) positive rate was negative; periodic acid−Schiff (PAS) stain positive rate was 4%; nonspecific esterase (NSE) was negative. Immunophenotypic of leukemia was HLA-DR, CD10, CD19, CD22, CD38, CD58, CD71, CD123, cCD79a, TdT expressed, consistent with acute B-lymphoblastic leukemia (B-ALL) immunophenotype (Fig.  3 ). ALL fusion gene screening detected ETV6 / RUNX1 fusion gene positivity. Karyotype was 46, XY. Therefore, the final diagnosis was B-lymphoblastic leukemia with positive ETV6 / RUNX1 fusion gene. Then, vincristine + daunorubicin + lasparaginase + dexamethasone (VDLD) remission induction chemotherapy was started immediately, and bone marrow morphology was repeated on day 33 of chemotherapy, which confirmed complete remission (CR). Comprehensive assessment was in the intermediate-risk group. The child was then successively given: cyclophosphamide, cytarabine, mercaptopurine, pegaspargase (CAML), high-dose methotrexate (HDMTX), and delayed intensive VDLD regimen chemotherapy. Regular intrathecal triple therapy was also administered to prevent CNS leukemia. The child had sustained CR of bone marrow on reexamination, and cerebrospinal fluid biochemistry, routine, and cell morphology were normal; he is still undergoing follow-up HDMTX intensive chemotherapy (Table  4 ). As leukemia gradually resolved, the child recovered from severe hypokalemia and acidosis, and his vital signs were stable, and he was in good general condition. There was no evidence of blast infiltration into other organs.

Kidney pathology image of the patient. Black arrows point to diffuse lymphocytic infiltrates in the renal interstitium

More frequently disease-causing gene mutation of Sanger sequencing verification result. A Second-generation sequencing of the gene revealed a novel mutation c.2689A > G in the SCN4A gene (the arrow shows the mutation site).  B The child's father, mutations in 163 G > A, peak figure can be displayed as G > C > T A or its reverse complementary sequence

Bone marrow cell morphology analysis report

In this case, the patient presented with diabetes insipidus and refractory hypokalemia as the initial symptoms, and there were no positive signs of leukemia on physical examination. After a series of complex tests, the diagnosis of B-lymphoblastic leukemia/lymphoma was finally confirmed. Previous literature reports have suggested that impaired kidney function and enlarged kidneys are common initial manifestations of ALL. However, acute lymphoblastic leukemia with kidney infiltration presenting as nephrogenic diabetes insipidus is rare. This case suggests that clinicians should try to explain multiple clinical manifestations as much as possible from a holistic perspective, broadening our understanding of ALL.

At the beginning of the disease, children with ALL have a rare initial onset with renal enlargement or a urinary symptom, such as edema, hematuria, hypertension, oliguria, or polyuria [ 8 , 9 ]. A study showed 24 ALL children with renal damage as the first symptom, accounting for 2.33% of the newly treated children in the same period, being very rare in clinical practice. The first symptom was edema (75.0%), and more than half of them (58.3%) were first diagnosed in a nonhematology department [ 10 ].

Meanwhile, diabetes insipidus caused by leukemia is rare and can be divided into central diabetes insipidus and nephrogenic diabetes insipidus. The former is caused by blasts infiltrating the nervous system, which is CNS leukemia. According to research by Abraham Kornberg et al. , leukemia can infiltrate the pituitary gland or hypothalamus causing central diabetes insipidus, respectively [ 11 ]. Nephrogenic diabetes insipidus due to renal infiltration of blasts is rare. One case has been reported by Dezhi Li et al. , which describes a 19-year-old man suffering from weakness, polydipsia, and polyuria for 1 month [ 12 ]. Nephrogenic diabetes insipidus was diagnosed by water deprivation and pressurization test. Combined with the findings of immunophenotypic of bone marrow examination, cerebrospinal fluid cytology, and abdominal ultrasonography, the final diagnosis of precursor B-cell ALL with renal infiltration was confirmed. Foresti reported on a 69-year-old male patient with 4-month history of polyuria and polydipsia. Plasma vasopressin levels were undetectable, and dehydration tests yielded abnormal results. These findings led to a diagnosis of central diabetes insipidus. Additionally, hematological assessments revealed acute monocytic leukemia. A potential link between the hematological and endocrine disturbances was proposed, with post mortem histological examinations revealing leukemic infiltration of the pituitary stalk [ 13 ]. In this case, the initial symptoms of the patient were diabetes insipidus and refractory hypokalemia, and there were no leukemia-related positive signs from the physical examination. At that time, acute glomerulopathy was highly suspected, but renal biopsy showed lymphocyte infiltrates. Central diabetes insipidus was excluded by diagnostic examinations, and the diagnosis of nephrogenic diabetes insipidus with renal tubular acidosis was then confirmed, while bone marrow aspiration and renal biopsy confirmed the diagnosis of ALL. This case bears resemblance to the study conducted by Dezhi Li, but the child’s examination detailed in this report is notably more comprehensive, as renal biopsy vividly demonstrated tumor cell infiltration in the kidneys. Research indicates that diabetes insipidus stemming from central nervous system leukemia is more prevalent than that caused by renal involvement in leukemia. Foresti elaborated on the association between acute monocytic leukemia and central diabetes insipidus. Although the initial symptoms of acute lymphoblastic leukemia (ALL) are varied, inaccuracies in diagnosis can exacerbate the condition, underscoring the importance of prompt and precise diagnosis and treatment. This case offers a novel perspective on the urinary system as an initial indicator of the disease. ALL should be considered in the differential of unexplained renal injury, even if blood investigations are normal. Special attention should also be paid to examination of the liver, spleen, and lymph nodes. The peripheral blood cells should be submitted for morphological analysis, and bone marrow biopsy or renal biopsy should be performed as soon as possible to confirm the diagnosis. Nevertheless, this study has its limitations. It documents a rare instance of acute lymphoblastic leukemia presenting primarily with renal diabetes insipidus. The generalizability of findings from a single case is minimal, necessitating further case studies for validation.

This paper reports a case with nephrogenic diabetes insipidus as the initial symptoms and analyzes the details of the case. Clinicians’ understanding of ALL is widened by the evidence that ALL renal infiltrates can cause nephrogenic diabetic insipidus.

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The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

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This study was supported in part by grants from Study on the correlation between FKBP4 gene polymorphism and the therapeutic effect of glucocorticoid in children with systemic lupus erythematosus (2022D01C466).

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Ning Qu analyzed and interpreted the patient data regarding the hematological disease and the transplant. Hongtao Zhu performed the histological examination of the kidney, and was a major contributor in writing the manuscript. All authors read and approved the final manuscript.

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Qu, N., Zhu, H. Acute lymphoblastic leukemia with nephrogenic diabetes insipidus as the first symptom: a case report. J Med Case Reports 18 , 421 (2024). https://doi.org/10.1186/s13256-024-04710-0

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Leukaemia, lymphoma, and multiple myeloma mortality after low-level exposure to ionising radiation in nuclear workers (INWORKS): updated findings from an international cohort study

In a new article, researchers from the International Agency for Research on Cancer (IARC) and partner institutions in France, Spain, the United Kingdom, and the USA who are studying the effects of persistent exposure to low doses of ionizing radiation on workers in nuclear facilities report an increase in mortality due to haematological neoplasms. The findings were published in The Lancet Haematology .

The scientists found a positive association between long-term low-dose exposure to ionizing radiation and mortality due to leukaemia (excluding chronic lymphocytic leukaemia [CLL]), chronic myeloid leukaemia, acute myeloid leukaemia, myelodysplastic syndrome, and multiple myeloma.

The scientists estimated that the mortality rate due to leukaemia increased by more than 250% per gray (Gy) of exposure (excess relative rate [ERR] per Gy, 2.68; 90% confidence interval, 1.13–4.55) and found the excess rate to be reasonably described by a linear dose–response model. The dose of radiation exposure typically accrued by workers in the study was low, at 0.016 Gy, and absolute mortality from leukaemia attributable to radiation exposure in the study population was estimated at 13 excess deaths per 100 000 workers over a period of 35 years (compared with 250 deaths expected from non-CLL leukaemia among those unexposed to radiation). A gray is a unit of the radiation quantity absorbed dose that measures the energy deposited by ionizing radiation, defined as the absorption of one joule of radiation energy per kilogram of matter.

Studies of people exposed to low doses of radiation add to our understanding of radiation risks at the exposure levels of contemporary concern, and thus can inform radiation protection efforts. The ERR per Gy for leukaemia mortality estimated in this study is close to the excess rate previously estimated in the Radiation Effects Research Foundation Life Span Study of Japanese atomic bomb survivors, which was 2.75 per Gy.

This new article is a major update to the International Nuclear Workers Study (INWORKS), which followed up 309 932 workers in the nuclear industry for an average of nearly 35 years, resulting in a total follow-up of 10.7 million person-years. The workers were employed at nuclear sites in France, the United Kingdom, and the USA and were monitored with radiation badges, which measured their exposure to radiation.

IARC has been coordinating and leading pooled studies of nuclear workers for more than 35 years. The INWORKS study partners are IARC, the Institut de Radioprotection et de Sûreté Nucléaire (France), the UK Health Security Agency, the National Institute for Occupational Safety and Health (USA), the Instituto de Salud Global de Barcelona (Spain), and the University of California, Irvine Joe C. Wen School of Population & Public Health (USA).

Leuraud K, Laurier D, Gillies M, Haylock R, Kelly-Reif K, Bertke S, et al. Leukaemia, lymphoma, and multiple myeloma mortality after low-level exposure to ionising radiation in nuclear workers (INWORKS): updated findings from an international cohort study Lancet Haematol , Published online 30 August 2024; https://doi.org/10.1016/S2352-3026(24)00240-0

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Read “Cancer mortality after low dose exposure to ionising radiation in workers in France, the United Kingdom, and the United States (INWORKS): cohort study”, a related article describing the association between exposure to ionizing radiation and mortality due to solid cancers

Published in section: IARC News

Publication date: 2 September, 2024, 0:30

Direct link: https://www.iarc.who.int/news-events/leukaemia-lymphoma-and-multiple-myeloma-mortality-after-low-level-exposure-to-ionising-radiation-in-nuclear-workers-inworks/

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Understanding leukaemia: risk factors, symptoms and treatment

02 September, 2024 By John Knight and Yamni Nigam

This article, the second in our series on disorders of the blood and bone marrow, explores the main forms of leukaemia. This is a Self-assessment article and comes with a self-assessment test

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Red bone marrow acts as the organ of haematopoiesis, generating the formed elements of blood. Stem cells in red bone marrow differentiate into two lineages. The myeloid lineage is the origin of erythrocytes, neutrophils, basophils, eosinophils, monocytes and platelets. The lymphoid lineage is the origin of lymphocytes, which are essential to specific immune responses and antibody production. Leukaemias occur due to genetic/age-related changes or damage to red bone marrow, and are classified into myeloid or lymphoid forms depending on the lineage affected. Acute forms of leukaemia develop rapidly, while chronic forms develop slowly over time. This article, the second of a series on the pathophysiology of the blood and bone marrow, discusses the common leukaemias.

Citation: Knight J, Nigam Y (2024) Understanding leukaemia: risk factors, symptoms and treatment. Nursing Times [online]; 120: 9.

Authors: John Knight is associate professor, Yamni Nigam is professor; both at the School of Health and Social Care, Swansea University.

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Introduction

Leukaemias are cancers featuring malignant and abnormal cells in the bone marrow and circulating in the blood. This second article in our series on the pathophysiology of the blood and bone marrow discusses common forms of leukaemias.

Red bone marrow and haematopoiesis

Red bone marrow functions as the major organ of haematopoiesis (blood cell production) and is responsible for generating the formed elements of blood: erythrocytes (red blood cells), leukocytes (white blood cells) and small cellular fragments called platelets that are essential to blood clotting (Knight et al, 2024).

In children , red bone marrow is found throughout the skeleton but, as the skeleton matures, the red bone marrow is gradually replaced with yellow bone marrow (fat) in most of the long bones of the arms and legs. In adults, most red bone marrow resides in the central portions of many flat bones, including the ribs, sternum, vertebrae and pelvic girdle, with smaller amounts in the epiphyses of larger long bones such as the femur and humerus.

Stem cell lineages

The multipotent stem cells (undifferentiated cells capable of becoming multiple cell types) in the red bone marrow differentiate into two lineages (populations) of cells (Knight et al, 2024):

• Myeloid lineage;
• Lymphoid lineage (Fig 1).

Myeloid lineage

This is the origin of most of the formed elements of the blood including:

• Erythrocytes – the most common blood cell, these facilitate the transportation of oxygen and carbon dioxide. Initially nucleated (proerythrocytes), they subsequently lose their nuclei to allow them to store more haemoglobin (more details are given in the first article in this series);
• Neutrophils – the most common leukocyte (50-60% of leukocytes), these have a distinctive multi-lobed nucleus (Fig 1). Their primary function is to phagocytose (engulf) pathogenic micro-organisms and cellular debris. Neutrophils are capable of leaving the blood and moving into inflamed and infected areas of the body;
• Basophils – the rarest leukocyte (around 0.5-2% of the total population), these produce histamine, a potent inflammatory mediator, and heparin, a natural anticoagulant;
• Eosinophils – characterised by their bi-lobed nucleus (Fig 1), these account for around 1-4% of the leukocyte population. They are involved in the destruction of parasites (for example, worms) and regulating and dampening down the inflammatory response;
• Mast cells – these are similar in structure and function to basophils, but do not circulate in the blood. Mature mast cells reside in virtually all solid organs and tissues, and have a primary role of generating histamine;
• Monocytes – the largest leukocyte, with a characteristic crescent/kidney-shaped nucleus (Fig 1), these account for 2-9% of leukocytes. Like the more common neutrophils, monocytes are phagocytic cells that have a key role in removing pathogens. They typically circulate for ~24 hours before leaving the blood vessels and entering the solid tissues of the body. After this emigration, monocytes mature into much larger cells called macrophages, which can patrol tissues (as wandering macrophages). Some macrophages will eventually anchor themselves into position in a tissue, becoming fixed macrophages. The reticuloendothelial system (RES) is a system of fixed macrophages throughout the body. Together, the RES and the mobile wandering macrophages play an essential role as sentinel cells that continually monitor the body for potential infection;
• Platelets – in the red bone marrow reside large cells called megakaryocytes. These have an unstable cytoplasm and are continually shedding cellular fragments called platelets or thrombocytes (Fig 1). Platelets play an essential role in haemostasis and blood coagulation (for more information, see the third article in this series).

Lymphoid lineage

The lymphoid lineage is the origin of the common leukocytes called lymphocytes. Accounting for 20-40% of the leukocyte population (Knight et al, 2024), these are subdivided into:

• B lymphocytes – also known as B cells, these mature in, and are released from, the red bone marrow. They produce a group of small proteins called antibodies (immunoglobulins). Antibodies are crucial to specific immune responses and bind to foreign materials, such as bacteria and viruses, marking them out for destruction;
• T lymphocytes – also known as T cells, these are released from the red bone marrow and migrate to the thymus gland. Here they mature before being released into the general circulation. The term ‘T cell’ reflects their maturation in the thymus. T cells have multiple roles, including helping B cells to generate antibody (T helper) cells and fine-tuning immune responses;
• Natural killer cells – these specialised lymphocytes are involved in the detection and destruction of malignant and virally infected cells.

Leukaemias are among the multiple pathologies affecting bone marrow. Others include lymphomas and multiple myeloma, which are covered in the fourth article in this series.

Leukaemias are the twelfth most common cancer in the UK, accounting for 3% of all new cancer cases (Cancer Research UK, no date a). They are malignancies that affect the red bone marrow, leading to blood cell abnormalities and compromised immune responses. Broadly, they can be subdivided into myeloid or lymphoid leukaemias, according to the cell lineage that is affected (Fig 2).

Myeloid leukaemias

As the name implies, myeloid leukaemias primarily affect cells derived from the myeloid lineage.

Acute myeloid leukaemia Although often referred to as a rare cancer, acute myeloid leukaemia (AML) is the most common acute leukaemia in adults (Ladikou et al, 2022), particularly those aged >75 years (NHS, 2022). AML is also the second most common form of leukaemia in children and, in the UK, ~3,100 people are diagnosed with AML each year (NHS, 2022).

Causes of the disease remain unclear, but the following have been associated with an increased risk of AML:

• Benzene exposure – a chemical found in cigarette smoke, petrol and used in many industrial processes;
• Previous cancer treatments – including chemotherapy and radiotherapy;
• Certain other blood/marrow disorders – including myelofibrosis, myelodysplasic syndromes and polycythaemia vera (discussed later in this article);
• Genetic predisposition – genetic and chromosomal disorders, such as Fanconi anaemia and Down syndrome (NHS, 2022).

AML is also associated with mutations in the genes involved in haematopoiesis of the myeloid lineage, and is characterised by clonal expansion and the appearance of abnormally large numbers of myeloblast cells in the blood. This allows diagnosis to be confirmed using blood smears (viewed under a microscope) and other haematological tests (Ladikou et al, 2022).

Symptoms of AML are similar to those of most leukaemias (Fig 3). Key early symptoms are feeling tired, washed out and breathless with a pallid complexion; this reflects anaemia due to a decrease in healthy erythrocytes derived from the myeloid lineage. As the leukocyte populations are also affected, infections become more likely, while lack of platelets (also derived from the myeloid lineage) can lead to nosebleeds, bleeding gums, appearance of tiny red spots (petechiae) on the skin and easy bruising (NHS, 2022).

Treatment of AML includes chemotherapy and, where appropriate, bone marrow transplants (NHS, 2022). Cure rates are ~40% in patients aged <60 years; however the prognosis remains poor in older patients, with only ~15% aged ≥60 years currently cured (Ladikou et al, 2022).

Myelodysplasic syndromes

Myelodysplasic syndromes (MDS) are a group of bone marrow malignancies in which the myeloid lineage does not generate sufficient healthy cells (Li et al, 2022); they are often referred to as acquired bone marrow failure syndromes (Steensma, 2015). Like other myeloid leukaemias, MDS usually affects older patients; patients’ median age at diagnosis is 75.7 years and incidence in the UK has been reported at 3.72 per 100,000 population each year (Killick et al, 2021).

Age is the major risk factor, with 85-90% of cases associated with age-related damage to the myeloid marrow stem cells (Steensma, 2015). Other potential causes include ionising radiations (for example, radiotherapies) and exposure to hydrocarbons such as benzene (for example, from car emissions) (Steensma, 2015).

MDS typically causes cytopaenia (lack of circulating blood cells); this may manifest as anaemia (decreased erythrocytes), leukopaenia (decreased leukocytes), thrombocytopaenia (decreased platelets) or a combination of these (Sekeres and Taylor, 2022). According to the NHS (2021) the World Health Organization (WHO) currently recognises three major forms of MDS:

• Single-lineage dysplasia (previously termed refractory anaemia);
• Multilineage dysplasia (formerly cytopenia);
• Excess blasts (formerly refractory anaemia with excess blasts).

Fig 3 shows the common symptoms of leukaemia. Symptoms are largely determined by the cell types of the myeloid lineage that are affected (NHS, 2021). If erythropoiesis (production of red cells) is affected, this results in anaemia and tiredness and breathlessness. If leukopoiesis (production of white cells) is affected, increased infections are more likely. If thrombopoiesis (production of platelets) is affected, there is increased susceptibility to excessive bleeding (including nosebleeds) and easy bruising.

MDS is recognised as an unstable disease and may progress in severity. It is characterised by the presence of <20% blast cells (immature undifferentiated cells) in the red bone marrow. This number can increase with an evolution to AML, with Steensma (2015) citing the WHO definition of at least 20% blast cells in the red bone marrow.

Treatments will depend on the cells affected, but the aim is to restore blood cell numbers to as close to normal as possible. Interventions include:

• Erythropoietin – to help treat anaemia by increasing erythrocyte numbers;
• Blood transfusions – to restore numbers of erythrocytes and platelets;
• Granulocyte colony stimulating factor – to increase granular leukocytes to help immune function.

Antibiotics may also be used to help with infections. If there is a high risk of transformation to AML, chemotherapy/radiotherapy and bone marrow transplants may be considered (NHS, 2021).

The prognosis for people with MDS varies from many years to months and is related to the likely progression to AML; five-year survival rates for MDS are ~36.9% (Leukemia and Lymphoma Society, no date).

Myeloproliferative neoplasms

In many ways, myeloproliferative neoplasms are the polar opposite of MDS. They are characterised by excess blood cell production, with elevated numbers of erythrocytes, leukocytes or platelets released into the blood.

Polycythaemia vera Polycythaemia vera (PV) is myeloproliferative disorder caused by a mutation in the Janus kinase 2 (JAK2) gene, leading to excessive production and release of erythrocytes into the circulation (NHS, 2023a). This results in an elevated haematocrit score (Fig 4). PV has a median age of presentation of 61 years, with only 10% of diagnosed cases in people age <40 years; reported incidence in Europe is 0.4-2.8% per 100,000 people each year (National Institute for Health and Care Excellence (NICE), 2023).

Patients with PV typically present with symptoms of fatigue, insomnia and difficulty concentrating, or are found to have elevated haemoglobin and haematocrit scores in routine blood tests. Other symptoms include reddened skin rash with itch (pruritus), particularly on contact with water, and enlargement of the spleen (Fox et al, 2021).

WHO criteria for a PV diagnosis, as cited by Tefferi and Barbui (2020), are:

• Haemoglobin >16.5 g/decilitre (dL) (one tenth of a litre) in men and >16g/dL in women, haematocrit >49% in men and >48% in women, or increased red blood cell mass;
• Bone marrow trilineage proliferation with pleomorphic (variations in size and shape of cells or their nuclei) mature megakaryocytes;
• Presence of JAK2 mutation.

The same authors cite WHO minor criterion as including subnormal haematopoietin level.

A major problem with PV is elevated erythrocyte numbers increasing blood viscosity. This reduces the velocity of blood flow, markedly increasing the risk of thrombosis and thromboembolic events. These are the most common complications of PV and include myocardial infarctions, thromboemolic strokes, deep vein thromboses and pulmonary emboli (Verstovsek et al, 2023; Griesshammer et al, 2019). Thrombosis and thromboembolic events have been reported in 39-41% of patients with PV and frequently led to initial diagnosis of the disease (Griesshammer et al, 2019).

Without treatment, death typically occurs within two years, most commonly due to a major thromboembolic event (Fox et al, 2021). Common treatments include phlebotomy, which aims for haematocrit level of <45%; this typically involves taking 450-500ml of blood monthly and a daily low dose of aspirin (40-100mg) (Fox et al, 2021). In higher-risk patients, cytoreductive therapies to reduce the number of circulating erythrocytes may be necessary as outlined below:

• Hydroxyurea and busulfan – chemotherapeutic drugs that reduce stem cell proliferation;
• Ruxolitinib – targeted cancer therapy that inhibits the dysregulated JAK-2 signalling associated with PV;
• Pegylated interferon-alfa – an immune modulator that induces disease remission (Fox et al, 2021).

With treatment, median survival is around ~15 years, but patients aged ≤40 years at diagnosis typically survive for >35 years (Tefferi and Barbui, 2023).

Essential thrombocythaemia

Essential thrombocythaemia (ET), also known as essential thrombocytosis, is a relatively rare myeloproliferative disease characterised by the excessive production of platelets. It is associated with mutations in three genes: JAK2, calreticulin (CALR) and myeloproliferlive leukaemia oncogene (MPL) (Ashorobi and Gohari, 2023).

WHO major criteria for diagnosis of ET, as cited by Tefferi and Barbui (2020), are:

• Platelets – ≥450 x 109/L;
• Bone marrow megakaryocyte proliferation and loose clusters;
• Not meeting WHO criteria for other myeloid neoplasms;
• JAK2/CALR/MPL mutated (Tefferi and Barbui, 2020).

The same authors cite WHO minor criterion as the presence of another clonal marker or no evidence of reactive thrombocytosis.

In the UK, ET has a reported incidence of ~2,700 cases per year, with ~13,000 people currently living with the disease (Blood Cancer UK, 2023).

The excessive numbers of platelets lead to hypercoagulability and increased risk of serious thrombotic and haemorrhagic events. Other symptoms (and the percentage of patients affected) include:

• Fatigue (90.3%);
• Insomnia (58%);
• Sad mood (57.3%);
• Inactivity (53.7%);
• Early satiety (53.2%);
• Night sweats (51.3%);
• Bone pain (45.2%);
• Fever (17%);
• Weight loss (23.4%) (Accurso et al, 2020).

A small proportion of patients may progress to other myeloproliferative disorders, such as PV and AML (Accurso et al, 2020).

Low-risk patients (aged <60 years old with no history of thrombosis) are usually managed with aspirin. For higher-risk patients, low-dose aspirin is usually combined with cytoreductive therapies. This includes drugs routinely used in managing PV, such as hydroxyurea and pegylated interferon therapy; also commonly used is anagrelide, which reduces platelet numbers (Ashorobi and Gohari, 2023).

Compared with other myeloproliferative disorders, ET has a favourable prognosis with a 10-year survival rate of ~89% (Accurso et al, 2020).

Chronic myeloid leukaemia

Chronic myeloid leukaemia (CML), also called chronic myelogenous leukaemia, is a rare myeloproliferative disorder with ~836 people diagnosed each year in the UK (Cancer Research UK, no date b).

CML is commonly diagnosed after the age of 65 years, although it can occur at any age (NHS, 2023b). At diagnosis, CML can be at one of three phases depending on the number and location of leukaemia stem cells (LSCs):

• Chronic phase – LSCs confined to bone marrow;
• Accelerated stage – typically after 1-2 years of the chronic phase and characterised by enlargement of the spleen and often febrile response. Most patients will pass through the accelerated phase before entering the blast phase;
• Blast stage – also known as the acute phase or blast crisis phase, this is characterised by LSCs infiltrating other areas of the body (including the liver, lymph nodes, central nervous system and lungs). This stage closely resembles AML and, without treatment, has a typical survival time of 2-3 years (Rinaldi and Winston, 2023).

Of patients with CML, ~90% will be diagnosed in the chronic phase (NICE, 2022).

Symptoms of CML are typical to those of most other leukaemias, and include:

• Fatigue/anaemia;
• Easy bruising/bleeding;
• Repeated and prolonged infections;
• Bone/joint pain;
• Night sweats;
• Poor appetite and weight loss (NHS, 2023c).

Treatment options vary according to the stage of the disease, but usually involve targeted therapies centred around tyrosine kinase inhibitors (for example, imatinib, dasatinib or asciminib). These medications restrict abnormal cell division and the release of abnormal cells from the bone marrow (NICE, 2022). Chemotherapy and bone marrow transplants may also be an option in some patients (NHS, 2023b).

CML has a good prognosis, with >90% of patients aged <60 years and 80% aged ≥60 years surviving for five years or more after diagnosis (Cancer Research UK no date b).

Lymphoid leukaemias

Lymphoid leukaemias are characterised by malignant changes in the lymphoid lineage of cells that give rise to the major groups of lymphocytes (shown in Fig 1). As with myeloid leukaemias, there are acute and chronic forms.

“Acute lymphoblastic leukaemia is the most common form of leukaemia seen in children”

Acute lymphoblastic leukaemia

Acute lymphoblastic leukaemia (ALL), also known as acute lymphocytic leukaemia, is a rare form of leukaemia affecting ~1.6 per 100,000 population, with ~760 new cases reported every year in the UK (Cancer Research UK, no date c). It is the most common form of leukaemia seen in children with those aged up to 4 years most at risk.

ALL is associated with chromosomal abnormalities; translocations (movement of chromosome segments between chromosomes) are usually present, and mutations to tyrosine kinase genes such as JAK2 are sometimes present. Other predisposing factors include exposure to ionising radiations, solvents, benzene and certain pesticides, infection with Epstein Barr virus or HIV, and chromosomal/genetic disorders such as Down syndrome and Bloom syndrome (Terwilliger and Abdul-Hay, 2017). Damage to stem cell DNA leads to the abnormal proliferation of immature lymphoid cells in the bone marrow, blood, and other organs and tissues (Brown et al, 2020).

The lymphoid lineage of cells is essential to specific immune responses that target single pathogens and help attack malignant and virally infected cells (Knight et al, 2024). ALL can be broadly subdivided depending on which populations of lymphocytes are affected:

• B cell ALL (B-ALL) – affects the antibody producing B cells (~85% of ALL cases);
• T cell ALL (T-ALL) – affects the T cell populations, which help B cells to produce antibodies and regulate specific immune responses (~10-15% of ALL cases);
• NK ALL – affects the NK cells, which attack malignant and virally infected cells (<1% of ALL cases) (Fujita et al, 2021).

Displacement of healthy stem cells by malignant cells produces symptoms related to anaemia, thrombocytopaenia (reduced platelets) and neutropaenia (reduced neutrophil numbers) (Puckett and Chan, 2023). Symptoms are the same as many forms of leukaemia and include:

• Fatigue/lethargy;
• Weight loss;
• Increased susceptibility to infections;
• Easy bruising/bleeding.

However, pain in the extremities and joints may be the only presenting symptom in children (Brown et al, 2020).

There are many treatment options, usually involving a three-phase chemotherapy treatment regime, which can take up to three years to complete. An induction phase uses medications such as vincristine, cyclophosphamide, cytarabine and corticosteroids to eliminate most malignant stem cells.

Induction is followed by a consolidation phase of intensified chemotherapy, including high-dose methotrexate with mercaptopurine, asparaginase or a repeat of the previous induction therapy.

Finally, a maintenance phase involves lower-dose chemotherapy, consisting of weekly methotrexate and daily mercaptopurine for an extended period to prevent relapse (NICE, 2017).

ALL prognosis is age dependent. People aged <15 years at diagnosis have a five-year survival rate of ~90%, falling to 65% in people aged 15-39 and 20% in those aged ≥40 years (Cancer Research UK, no date c).

Chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is the most common chronic leukaemia in older people and is rare below the age of 40 years; ~3,800 new cases are diagnosed each year (Cancer Research UK, no date d).

As with ALL, CLL occurs due to malignant cells affecting the lymphoid lineage but, as a chronic disease, it develops slowly over a relatively long period of time; most forms of CLL cannot be cured but can usually be effectively managed (NHS, 2023b).

CLL affects the B lymphocyte (B cell) lineage, leading to the accumulation of large numbers of malignant B cells in the bone marrow. Malignant B cells can also accumulate in the lymphoid organs and tissues, including the spleen and lymph nodes, leading to swelling; CLL manifesting in this way is also known as small lymphocytic lymphoma (Mukkamalla et al, 2023).

Of patients with CLL, ~70% are diagnosed through incidental discovery of lymphocytosis (elevated lymphocyte numbers) in routine blood tests and will have no apparent symptoms. Of those with symptoms, ~50% will present with lymphodenopathy (enlarged lymph nodes), 20-50% will show enlargement of the spleen and/or liver, and 5-10% will have unintended weight loss (Shadman, 2023). Other symptoms include fever, drenching night sweats and extreme fatigue (Shadman, 2023).

Some patients with CLL will initially receive no treatment, and a ‘watchful waiting’ approach will be adopted (Mukkamalla et al, 2023). Indeed, as the median age of diagnosis is ~70 years, ~30% of all CLL patients will never receive treatment (Shadman, 2023).

Treatment is usually initiated in patients with active symptomatic disease (Mukkamalla et al, 2023), and includes ibrutinib, acalabrutunib, and zanubrutinib. These inhibit B cell proliferation and, in most cases, will result in disease remission. Although CLL is regarded as an incurable disease without a successful bone marrow transplant, many patients die with the disease rather than from it (Shadman, 2023).

As with ALL, CLL prognosis is age dependent. For those aged <60 years at the time of diagnosis, five-year survival is ~95%, falling to 90% in people aged 60-69 years, 80% in those aged 70-79 years and 5% in people aged ≥80 years (Cancer Research UK, no date d).

This article has explored the main forms of leukaemia, highlighting risk factors, symptoms and treatments. AML is the most common acute leukaemia in adults and ALL the most common acute leukaemia in children. CLL is the most frequent chronic form in older people.

• The third article in this series will explore coagulopathies, which affect the ability of the blood to clot.
• Leukaemias are cancers affecting the red bone marrow, leading to blood cell abnormalities and compromised immune responses
• There are two forms of leukaemias: myeloid and lymphoid
• Leukaemias can cause anaemia due to impaired red blood cell production
• Myelodysplasic syndromes are characterised by the reduced production of healthy blood cells
• Myeloproliferative disorders are characterised by excess blood cell production

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Understanding the causes, symptoms and treatments of anaemias.

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• Case Report
• Open access
• Published: 02 September 2024

A case report of prolonged viral shedding of SARS-CoV-2 in a patient who receive ibrutinib for CLL therapy

• Siyuan Ma 1   na1 ,
• Dong Wei 2 , 3   na1 ,
• Weiwei Hu 1 ,
• Yi Zhang 1 ,
• Xiaohua Chen 1 &
• Jie Chen 1  

BMC Infectious Diseases volume  24 , Article number:  895 ( 2024 ) Cite this article

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Patients on B cell immunosuppressive treatments have been shown to have persistent infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this report, a woman treated with ibrutinib for chronic lymphocytic leukemia experienced more than 40 days of coronavirus disease 2019 (COVID-19) infection. Unexpectedly, her peripheral blood experiments showed a normal SARS-CoV-2-specific antibody level and a relatively elevated percentage of CD19 + B cells, while an obvious decrease in the percentages of NK cells, CD4 + T cells and CD8 + T cells. Further SARS-CoV-2-specific T cell analysis in this patient indicated a significant decrease in the percentage of SARS-CoV-2-specific IFN-γ, TNF-α or IL-2 producing CD4 + T or CD8 + T cells. Most notably, ten days after the cease of ibrutinib, the PCR for SARS-CoV-2 turned negative and the reduced proportions of peripheral CD4 + T cells and CD8 + T cells recovered. Our research predicted that the depleted B-cell function therapies may play considerable role in the development of long COVID-19 and the abnormal T-cell subset distribution might be the underlying mechanism.

Peer Review reports

Introduction

The duration of viral shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is usually less than two weeks. Patients with hematological malignancies, especially chronic lymphocytic leukemia (CLL) are often on therapeutic drugs that suppress the immune system, putting them at a particularly high risk for persistent viral replication or severe secondary infections when infected with SARS-CoV-2 [ 1 , 2 , 3 ]. Ibrutinib is a potent Burton’s tyrosine kinase (BTK) inhibitor and has been used in different B cell malignancies, including CLL [ 4 , 5 , 6 , 7 ]. It has aroused heated clinical and scientific debate about whether the CLL patients infected with COVID-19 should maintain or discontinue ibrutinib treatment. In this scenario, the scholars who advocated ibrutinib discontinuation believed that the immunosuppressive activity of ibrutinib might bear responsibility for viral persistence and exacerbate secondary infection in susceptible patients [ 8 , 9 , 10 ]. The decision to continue ibrutinib was supported by data suggesting that BTK inhibition might mitigate the cytokine storm which was associated with a series of complications, including lung injury, DIC, and myocardial complications [ 8 , 11 , 12 ].

Here, we describe a patient who developed persistent symptomatic COVID-19 infection for more than forty days. The patient had a past history of CLL for which she had been receiving ibrutinib monotherapy for two years prior to the onset of symptoms of COVID-19. Initially admitted to another hospital and during twenty-day treatment period, the patient was instructed to continue taking ibrutinib to prevent tumor recurrence. However, Polymerase Chain Reaction (PCR) from nasopharyngeal specimens remained positive results for SARS-CoV-2. Contrary to previous studies that indicated decreased B cell levels and IgG levels during ibrutinib exposure [ 13 , 14 ], this patient’s B cell counts and neutralizing antibody profiles for COVID-19 were comparable to those of convalescent patients. After creasing ibrutinib and receiving comprehensive treatment for approximately ten days, the SARS-CoV-2 PCR on the nasopharyngeal swab turned negative result. Specifically, we observed a notable recovery in the percentages of NK cells, CD4+ T cells, CD8+ T cells. Our findings suggest that impaired antiviral T cell responses to SARS-CoV-2 may underlie viral persistence, and we discussed the scientific rationale for discontinuing ibrutinib in CLL patients with persistent COVID-19 infection.

Data were collected from electronic health records. The diagnosis of COVID-19 was confirmed through PCR analysis of nasopharyngeal swabs using the SARS-CoV-2 assay from Roche and the Cobas 6800/8800 system. Plasma samples were analyzed for SARS-CoV-2 IgG using pseudovirus neutralization assays as described previously [ 15 ]. To detect SARS-CoV-2-specific CD4 + and CD8 + T cells, peripheral blood mononuclear cells (PBMCs) were isolated from blood, and 1 × 10 6 PBMCs were stimulated with SARS-CoV-2 S protein in 200 μl in 96-well U-bottom plates (Corning, PA, USA) in a 5% CO 2 incubator at 37 °C for 20 h. To assess antigen-specific intracellular cytokine levels, including TFN-α, IFN-γ and IL-2, GolgiStop (BD Bioscience) was added 14 h after SARS-CoV-2 S protein stimulation, and the obtained cells were stained for phenotypic lymphocyte markers.

A 68-year-old woman without SARS-CoV-2 vaccination developed symptoms including fever, progressive shortness of breath, and cough. On January 17, 2023 (day 8 of her illness), she sought medical attention at a local hospital. The patient had previously been diagnosed with CLL and had been receiving ibrutinib as a maintenance therapy for two years prior to the onset of her COVID-19 symptoms. A chest computed tomography (CT) was performed at the local hospital on January 19, 2023, revealed multiple ground glass nodules in bilateral lungs, which were characteristic findings of COVID-19. A nasopharyngeal specimen tested positive for SARS-CoV-2 via PCR assay, and her oxygen saturation levels of peripheral artery were below normal. During her hospitalization, she continued to receive ibrutinib for her CLL as well as a 7-day course of azvudine (5 mg/day). She was also administrated low doses of corticosteroids (specific details were not available), and medications to alleviate cough, phlegm and asthma. Despite these treatments, her body temperature continued to fluctuated, and her respiratory symptoms progressively worsened. Remarkably, a follow-up chest CT scan on February 5 showed significant progression with bilateral diffuse ground glass opacities. Additionally, a new nodular lesion was identified in the upper lobe of the right lung. Subsequently, the patient was discharged from the local hospital on February 10 (day 32 of her illness) and transferred to our hospital on February 17 for further treatment.

A nasopharyngeal swab performed on February 17 continued to yield positive results by RT-PCR, with detection of the ORF1ab gene (Ct 28.51) and the N gene (Ct 23.10). Blood tests showed moderate leukocytopenia and thrombocytopenia (3.0*10^9/L and 82.0*10^9/L, respectively), lymphopenia(0.6*10^9/L), elevated levels of CRP (93.30 mg/L), interleukin-6 (11.7 pg/ml), and ferritin (1733.00 ng/ml), as well as significant hypogammaglobulinemia for IgA, IgG, IgM and IgE (0.268 g/l, 4.67 g/l, 0.182 g/l and < 19.4 IU/ml, respectively). The peripheral blood flow cytometry revealed a reduction in NK cells (7.16%), CD4 + T cells (17.71%), and CD8 + T cells (12.65%), though the CD4 + /CD8 + cell ratio was within normal range (1.4). Unexpectedly, the percentage of CD19 + B cells did not decrease (54.32%). Notably, serological testing showed that the levels of neutralizing antibodies in this patient for multiple Omicron variants were detectable and very high (Table  1 ), aligning with prior evidence of no significant decline in CD19 + B cell percentages. As seen in Table  2 , Table  3 and Table S1, after stimulated with the S protein of omicron or wild-type strain, we observed deficiency in naïve T cells and B cells, no significant differences in the proportion of T effector cells (Teff) or CD4 + , CD8 + effector memory T cells (Tem) and plasma cells between our patient and healthy controls who received two doses of the inactivated vaccine [ 15 ]. However, the percentage of SARS-CoV-2-specific IFN-γ-producing CD4 + T or CD8 + T cells was lower in our patient. All microbiologic tests for other respiratory pathogens showed negative results. The (1/3)-β-D-glucan test, GM test, latex agglutination test and the interferon-gamma release assay for tuberculosis were all negative. The levels of procalcitonin were normal and the blood culture was negative for fungus, bacteria, and anaerobes. At admission, treatment with dexamethasone was initiated, followed by a prolonged tapering corticosteroid regimen. Meanwhile, a second course of antiviral treatment (molnupiravir; 800 mg, twice a day, for 5 days) and intravenous piperacillin-tazobactam were administered. She also received supportive and symptomatic treatments including intravenous immunoglobulin, low-molecular-weight heparin, leucogen and ambroxol hydrochloride tablets (Table  4 ). After an interdisciplinary discussion with hematologist, the patient was asked to cease ibrutinib on the second day of her admission. The enhanced chest CT examination on February 20 showed bilateral diffuse ground glass opacities and the lesions in the dorsal segment of the left lower lobe trended towards consolidation. A lump was identified in the upper lobe of the right lung, with a diameter of about 3.2 cm and obvious enhancement at the edge. Burr-like changes and pleural traction were seen at lower edge of the lump (Fig.  1 ). For this reason, we consulted an interventional radiologist for their opinion about whether it was necessary to perform a puncture examination on the lump and were advised to strengthen the anti-infection therapy first. Therefore, Piperacillin-Tazobactam was replaced with imipenem on the fifth day of hospitalization. The SARS-CoV-2 RNA became undetectable on February 24 (the 8th day of her admission, 43 days after her initial symptoms), and remained negative on February 28. The follow-up peripheral blood flow cytometry on February 28 revealed a recovered NK cells (14.19%), CD4 + T cells (29.74%), CD8 + T cells (45.09%), and an inversion of the ratio of CD4 + /CD8 + cells (0.81). Significantly, the percentage of CD19 + B cells returned to 9.71%. The neutralizing antibody levels for SARS-CoV-2 detected in the repeated serologic test on February 28 are comparable to those on February 18 (Table  1 ). After about 10 days of treatment including the anti-infection therapy (Imipenem and Cilastatin Sodium, 1 g, iv, every 8 h a day), intravenous immunoglobulin (5 g, ivgtt, once a day), glucocorticoid (Dexamethasone, 3 mg, iv, once a day, for three days, then switch to prednisone acetate; 15 mg, po, once a day, tapering by 1 tablet every 3 days),  low-molecular-weight heparin (4000 IU, ih, once a day) and ambroxol hydrochloride tablets (30 mg, po, three times a day), multiple indicators significantly improved in blood tests (Table 4). A follow-up CT scan on March 1 showed a resolution of bilateral inflammation. Moreover, the solid lesions in the upper lobe of the right lung transformed into air space opacities with gas-fluid levels (Fig.  1 ). Her general condition continued to improve, and she was finally discharged to home on March 2 (day 49) of her illness. Since then, the patient has been well without recurrence of symptoms and the PCR for SARS-CoV-2 remains to be negative. One month later, she became able to resume maintenance treatment with ibrutinib for CLL. Nowadays, the patient has been able to restart her active lifestyle.

Radiological characteristics on chest CT. A Enhanced chest CT images taken on February 20 revealed diffuse ground glass opacities in both lungs and partial consolidation in the dorsal segment of the left lower lobe. A nodular lesion of about 3.2 cm was found in the upper lobe of the right lung(red arrow). Left: images of the lung window; Right: images of the mediastinal window. B Follow-up enhanced chest CT was performed on March 1, indicating that the opacities were gradually resolving, and the solid lesions in the upper lobe of the right lung had shrunk to 2.8 cm and turned into air space opacities with fluid accumulation (red arrow). Left: images of the lung window; Right: images of the mediastinal window

The viral shedding of SARS-CoV-2 from upper respiratory specimens declines after initiation of symptoms and turned negative around 10 days after infection [ 2 ]. However, immunocompromised population, especially patients with hematologic malignancies have been reportedly shed the active virus for longer periods [ 16 , 17 ]. We described a case of a hematologic patient on ibrutinib monotherapy who experienced persistent COVID-19 infection. We ruled out reinfection or viral evolution, as all nasopharyngeal samples showed Ct values below 30 when SARS-CoV-2 RNA was positive, and neutralizing antibody levels mirrored changes in viral RNA clearance. Our investigation then focused on the patient's humoral and cellular immunity, revealing that despite a deficiency in naïve B cells, the patient exhibited levels of plasma cells and neutralizing antibodies comparable to those in recovered patients with similar disease courses. We also noted a temporary decrease in peripheral CD4 + and CD8 + T cells, which returned to normal after cessation of ibrutinib. Additionally, our patient showed reduced production of IL-2, IFN-γ and TNF-α in SARS-CoV-2-specific CD4 + and CD8 + T cells, indicating impaired T response.

The immunologic factors associated with chronic SARS-CoV-2 infection, such as CD4 + lymphopenia and B-cell aplasia, are distinct from those observed in acute severe COVID-19 infection. Hao et al. studied 104 COVID-19 patients and reported that decreased T cells and B cells were linked to prolonged viral shedding of SARS-CoV-2 [ 18 ]. Initially, we assessed our patient's neutralizing antibody profiles to explore whether ibrutinib, which can potentially impair humoral immunity, might influence the magnitude and duration of viral RNA shedding. The results showed that despite the patient's deficiency in naïve B cells, their levels of neutralizing antibodies against COVID-19 and plasma cell counts were normal. There is limited data on how BTKi affect neutralizing antibody levels in hematologic disorder patients post COVID-19 infection, but studies have shown increased Spike-IgG levels in serum after five COVID-19 vaccine doses in some ibrutinib-treated patients [ 19 ]. This variability may arise from patient heterogeneity or immune reconstitution, as Sun noted partial restoration of normal B cells and humoral immunity in CLL patients treated with ibrutinib [ 13 ]. Another possible reason for our patient’s high Spike-IgG levels could be that sampling for neutralizing antibody detection was performed one month after the initial onset of symptoms, a period was sufficient for activating humoral immunity and generating neutralizing antibodies. Furthermore, Ibrutinib significantly impacted the production of naïve B cells in this patient, while memory B cells and plasma cells were less affected.

Given the abnormal T-cell subset distribution and function reported in CLL [ 18 ], an alternative explanation for prolonged viral shedding in our patient could be an impaired antiviral T-cell response to SARS-CoV-2. We observed a decreased proportion of peripheral CD4 + and CD8 + T cells and a poor T-cell response to SARS-CoV-2 in our patient. These findings align with other studies that have indicated impaired T-cell responses in some patients with severe symptoms or poor viral control early in the disease course [ 20 , 21 ]. The compromised T-cell response in our patient's peripheral blood may be attributed to the tumor clone, which can disrupt T-cell subgroup balance and impair T-cell-mediated immune responses, or to ibrutinib reducing granzyme and IFNγ in CD8 + T cells [ 19 ]. This latter possibility is supported by the observed recovery of CD4 + and CD8 + T cells following cessation of ibrutinib. Further studies are necessary to confirm or differentiate between these potential causes of persistent viral shedding in more COVID-19 cases.

Many studies have reported persistent COVID-19 infection in patients with undergoing B-cell depletion therapy for hematologic malignancies, which can result in humoral defects [ 22 , 23 , 24 ]. However, our findings point to immune dysregulation characterized by impaired T cell responses as a causal factor in the development of long COVID-19 and developed infection lesions in the lungs. This also raises the controversy of whether ibrutinib therapy has an impact on the disease course and outcome in SARS-CoV-2 infected patients. We suggest that for such patients, it may be advisable to consider continuing BTKi therapy to manage underlying conditions only after controlling viral, bacterial, fungal, or other pathogenic infections. However, there are some contrary reports suggesting that BTKi can suppress excessive inflammatory responses and reduce the risk of severe infections of COVID-19 [ 8 ]. Hence, personalized treatment is essential for different patients. Future studies should aim to elucidate the immunologic defects associated with this clinical phenomenon, beyond the risk identified in our report related to BTKi treatment. Meanwhile, resuming antiviral treatment in immunocompromised patients with prolonged COVID-19 viral shedding should also be considered as a favorable factor for patient’s recovery. Taken together, our results seem to support the prognostic values of monitoring SARS-CoV-2-reactive antibodies and analyzing SARS-CoV-2-specific T cells in patients receiving ibrutinib for CLL therapy.

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Data availability

Data is provided within the manuscript or supplementary information files.

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Acknowledgements

We thank the patient for a retrospective re-interview and for providing epidemiologically related information relevant to this study.

This work was supported by the Shanghai Science and Technology Innovation Action Plan, experimental animal research project (No. 23141901900); Basic Research Project of the Sixth People's Hospital of Shanghai (No.ynms202306).

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Siyuan Ma and Dong Wei contributed equally to this work and should be considered co-first authors.

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Department of Infectious Diseases, Shanghai Sixth People’s HospitalAffiliated to, Shanghai Jiao Tong University School of Medicine , Shanghai, 200233, China

Siyuan Ma, Weiwei Hu, Min Xi, Yi Zhang, Xiaohua Chen & Jie Chen

Department of Infectious Diseases, Research Laboratory of Clinical Virology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases, Shanghai, People’s Republic of China

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S.M., D. W. and W. H. performed and analyzed experiments. M.X. and Y. Z. provided patient care, clinical information, and samples from the patient. X. C. and J. C. supervised the research. J. C., S. M. and D. W. wrote the manuscript, and all the co-authors revised, edited, and approved the manuscript.

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Correspondence to Xiaohua Chen or Jie Chen .

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Ma, S., Wei, D., Hu, W. et al. A case report of prolonged viral shedding of SARS-CoV-2 in a patient who receive ibrutinib for CLL therapy. BMC Infect Dis 24 , 895 (2024). https://doi.org/10.1186/s12879-024-09794-z

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Received : 10 December 2023

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Published : 02 September 2024

DOI : https://doi.org/10.1186/s12879-024-09794-z

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