Chronic Leukemia Research Articles

Diagnostic value and biological significance of CD71 in lymphoid disorders

Abstract Background The CD71 expression is tightly regulated by intracellular iron level, cell proliferation, or erythropoiesis at levels of receptor recycling, as well as transcriptional or posttranscriptional control. In the previous studies, CD71 was expressed by most of acute leukemia and chronic granulocytic leukemia in blast crisis with a variable density of expression. Only few studies have observed CD71 as a diagnostic and prognostic marker in cases of acute lymphocytic leukemia (ALL) as a type of acute leukemia. Therefore, our study aimed to evaluate the diagnostic and biological significance of CD71 in lymphoid disorders. Aim and objectives This study aimed to evaluate the diagnostic value and biological significance of CD71 in lymphoid disorders. Patients and methods The present research was carried out on 60 patients diagnosed with lymphoid disorders (benign lymphocytosis, ALL, CLL, lymphoma, and multiple myeloma) who presented to Assiut University Hospital from July 2020 till July 2021. Results CD71 expression was significantly higher in acute disorders (immature cell-type tumors of malignant lymphoid disorders) than in benign lymphocytosis and chronic disorders (immature cell-type tumors of malignant lymphoid disorders), with strong relation with the positivity of CD34 and TdT. Conclusion CD71 helps to differentiate between lymphoid disorders and further helps in discriminating the differentiation status of ALL. High expression of CD71 might reflect a much more aggressive and immature cell type. However, further prospective investigations are needed to document the possible relation of CD71 with response to treatment and relapse rate. Moreover, high expression of CD71 with clonal evolution in leukemia may predict the possibility of being an important molecular target in future therapy of acute leukemia.

Is It Still Possible to Think about HSP70 as a Therapeutic Target in Onco-Hematological Diseases?

The search for molecules to be targeted that are involved in apoptosis resistance/increased survival and pathogenesis of onco-hematological malignancies is ongoing since these diseases are still not completely understood. Over the years, a good candidate has been identified in the Heat Shock Protein of 70kDa (HSP70), a molecule defined as "the most cytoprotective protein ever been described". HSP70 is induced in response to a wide variety of physiological and environmental insults, allowing cells to survive lethal conditions. This molecular chaperone has been detected and studied in almost all the onco-hematological diseases and is also correlated to poor prognosis and resistance to therapy. In this review, we give an overview of the discoveries that have led us to consider HSP70 as a therapeutic target for mono- or combination-therapies in acute and chronic leukemias, multiple myeloma and different types of lymphomas. In this excursus, we will also consider HSP70 partners, such as its transcription factor HSF1 or its co-chaperones whose druggability could indirectly affect HSP70. Finally, we will try to answer the question asked in the title of this review considering that, despite the effort made by research in this field, HSP70 inhibitors never reached the clinic.

The oldest case of lymphoma? Insights from a XIII century fresco.

A fresco painted by an unknown artist in the mid XIII century and displayed in the “Gothic Hall” of the Four Crowned Saints' seclusion cloister in Rome (left panel) is interesting not only for its undisputed beauty, but also for a possible clinical enigma that can be seen on careful examination. The fresco shows a young woman with a readily detectable swollen area (roughly of walnut size) in the right cervical part of her neck (shown in higher magnification in the right panel). In the absence of other clinical information, our (independently reached) interpretation is that this may represent an early (perhaps the earliest) example of a lymphoma shown in a painting. Based on strict semeiotic principles, the size of the lymph node is sufficient to rule out, at least at a first glance, underlying infectious diseases such as mononucleosis or toxoplasmosis, which do not usually cause lymphadenopathy of that size. Similarly, chronic lymphatic leukemia may be excluded since it affects predominantly older patients. Yersinia pestis (the gram-negative coccobacillus causing plague or bubonic plague) infection is unlikely for at least two reasons: (a) the skin overlaying the swollen lymph node does not appear to be erythematous; (b) the plague pandemic, called “the black death”, arose in Crimea and then reached Europe in 1346,1 about a century after the fresco was painted. Mycobacterium tuberculosis may be suspected in this case since it typically involves latero-cervical region (i.e. cervical lymphadenitis also referred to as scrofula). However, a tuberculosis origin is unlikely in the woman in this painting since it gives rise to an early erythema of the overlaying skin,2, 3 which in this painting is lacking. These simple clinical considerations lead us to believe that the most probable cause of the swollen lymph node of this young woman painted in the mid XIII century is a lymphoma, and that this fresco is the earliest representation of such disease. Open Access Funding provided by Universita degli Studi di Ferrara within the CRUI-CARE Agreement.

Reverse Phase Protein Array Profiling Identifies Recurrent Protein Expression Patterns of DNA Damage-Related Proteins across Acute and Chronic Leukemia: Samples from Adults and the Children's Oncology Group.

DNA damage response (DNADR) recognition and repair (DDR) pathways affect carcinogenesis and therapy responsiveness in cancers, including leukemia. We measured protein expression levels of 16 DNADR and DDR proteins using the Reverse Phase Protein Array methodology in acute myeloid (AML) (n = 1310), T-cell acute lymphoblastic leukemia (T-ALL) (n = 361) and chronic lymphocytic leukemia (CLL) (n = 795) cases. Clustering analysis identified five protein expression clusters; three were unique compared to normal CD34+ cells. Individual protein expression differed by disease for 14/16 proteins, with five highest in CLL and nine in T-ALL, and by age in T-ALL and AML (six and eleven proteins, respectively), but not CLL (n = 0). Most (96%) of the CLL cases clustered in one cluster; the other 4% were characterized by higher frequencies of deletion 13q and 17p, and fared poorly (p < 0.001). T-ALL predominated in C1 and AML in C5, but both occurred in all four acute-dominated clusters. Protein clusters showed similar implications for survival and remission duration in pediatric and adult T-ALL and AML populations, with C5 doing best in all. In summary, DNADR and DDR protein expression was abnormal in leukemia and formed recurrent clusters that were shared across the leukemias with shared prognostic implications across diseases, and individual proteins showed age- and disease-related differences.

Two Cases of Juvenile Myelomonocytic Leukemia and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease

BackgroundMyelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an autoimmune demyelinating disorder that often manifests after infections or vaccinations. We report two patients who developed MOGAD out of eight patients with juvenile myelomonocytic leukemia (JMML) that has never been reported. MethodsWe investigated two patients with JMML who developed MOGAD among 127 patients with leukemia from 2012 to 2021. ResultsPatient 1 was treated for JMML and developed fever and impaired consciousness at two years and one month of age. Magnetic resonance imaging revealed high-intensity lesions in the left frontal and left occipital white matter. The serum anti-MOG antibody test was positive, while the test was negative in the stored serum 45 days before the onset of encephalopathy. He had relapse of MOGAD after steroid therapy and plasmapheresis. Patient 2, who was treated for JMML, became apathetic and mute at three years and seven months of age. Magnetic resonance imaging revealed left frontoparietal subcortical high-intensity lesions. Anti-MOG antibody at the onset of encephalopathy was positive, while it was negative in stored serum 57 days before and 47 days after the onset. ConclusionWe treated two patients who developed MOGAD out of eight patients with JMML and none with MOGAD out of 119 patients with acute lymphocytic leukemia, acute myelocytic leukemia, or chronic myelocytic leukemia. The activated autoimmune process via the RAS pathway abnormality may have led to the formation of the anti-MOG antibody and the onset of MOGAD. MOGAD can occur in children with JMML, and abnormalities of the RAS pathway possibly contribute to its onset.

Detection of some genetic mutations in H-Ras gene in acute and chronic leukemia

Leukemia is one of the most prevalent forms of cancer worldwide in men, women and children with high rate of mortality. Fifty samples of blood were collected from Iraqi patients who were clinically diagnosed by the consultants of the National Center of Hematology and Medical City and 25 healthy as a control group. By direct sequencing in Macrogen company for PCR products ; nineteen mutations were detected in codon 61 of H-ras gene in acute leukemia patients , 11 of them (57.89%) were substitutions and 8 (42.1%) were deletions. Moreover, the adenine found to involve in 14 (73.68%) of 19 mutations in AML detected in this study. Most of A abnormalities involve either trans version with C and T (7 transversions) or deletion of A. H-ras mutations were also detected in chronic leukemia patients, the H- ras mutations was 12 mutations including 7 (58.33%) deletions and 5 substitutions (41.66%) .

Evaluation of Bone Turnover Markers in Patients with Acute and Chronic Leukemia.

This study investigated different bone biomarkers (cross-linked carboxy-terminal telopeptide of type 1 collagen (CTX-1), pyridinoline (PYD), osteocalcin (OC), interleukin-6 receptor (IL-6R), calcium (Ca), and magnesium (Mg)) in terms of their metabolism in 4 different leukemia subtypes (ALL, AML, CLL and CML). The design was case control study with 30 controls and 60 cases of leukemia patients. Authors have reported many results regarding decrease as well as increase of specific bone biomarker under investigation with each leukemia subtype when compared to control. In addition, Authors reported correlations between each biomarker level and leukemia subtypes.

Successful Allogeneic Stem Cell Transplantation with Ruxolitinib Maintenance Therapy for CSF3R T618I Mutant Chronic Neutrophilic Leukemia

Successful Allogeneic Stem Cell Transplantation with Ruxolitinib Maintenance Therapy for CSF3R T618I Mutant Chronic Neutrophilic Leukemia

The Distribution and Phenotypes of Blood Groups in Hematologic Malignancies.

Blood groups are associated with duodenal ulcer, diabetes mellitus, and urinary tract infection. In some studies, a relationship was detected between hematologic and solid organ malignancies and blood groups. In this study, we investigated the frequency and phenotypes of blood groups (ABO, Kell, Duffy, Rh) in patients with hematologic malignancies. One hundred sixty-one patients with hematologic malignancy (multiple myeloma, chronic lymphocytic leukemia, and chronic myelocytic leukemia) and 41 healthy people were evaluated prospectively. We determined phenotypes and distribution of ABO, Rh, Kell, and Duffy blood groups in all cases. Chi-square test and 1-way variance analysis were used for statistical analysis. P < .05 value was considered statistically significant. In patients with multiple myeloma, the A blood group was statistically significantly more frequent than in the control group (P = .021). Rh negativity was found more frequent in patients with hematologic malignancy than the control group (P = .009). Kpa and Kpb antigen positivity were found statistically significantly less frequent in patients with hematologic malignancy (P = .013, P = .007; respectively). Fy (a-b-) and K-k+ phenotypes were higher in patients with hematologic cancer than in the control group (P = .045). We determined a significant relationship between hematologic malignancies and blood group systems. In our study, due to the low number of cases and few hematological malignancy types, extensive studies with more cases and more hematologic cancer types are needed.

Effectiveness of nirmatrelvir plus ritonavir treatment for patients with chronic lymphocytic leukemia during the Omicron surge

AbstractPatients with chronic lymphoid leukemia (CLL), even in the Omicron era and after vaccination, suffer from persistent COVID-19 infection, higher complications, and mortality compared with the general population. In this study, we evaluated retrospectively the effectiveness of nirmatrelvir + ritonavir among 1080 patients with CLL who were infected with severe acute respiratory syndrome coronavirus 2. Nirmatrelvir administration was associated with a reduction in COVID-19–related hospitalization or death by day 35. Specifically, the rate of COVID-19–related hospitalization or death in the treated group compared with the untreated group was 4.8% (14 out of 292) vs 10.2% (75 out of 733), respectively. Moreover, we report a 69% relative risk reduction in COVID-19–related hospitalization or death in patients with CLL at the age of ≥65 years. Multivariate analysis indicates that patients aged >65 years, patients who received heavy treatment (>2 previous treatments), patients with recent hospitalizations, intravenous immunoglobulin (IVIG) treatment, and comorbidity had significant improvement outcomes after treatment with nirmatrelvir.

Therapeutic effect of imatinib-loaded hydrogels on leukemia by inhibiting excessive apoptosis of white blood cells

Chronic myelocytic leukemia (CML) refers to a malignant proliferative disease of the bone marrow characterized by abnormalities of multipotent stem cells on the Philadelphia chromosome and accounts for approximately 20% of all leukemias. Imatinib is widely used in the treatment of CML patients because of its unique mechanism of action and high specificity. In this study, imatinib-loaded hydrogels were prepared from the natural polysaccharide hyaluronic acid and carboxymethyl chitosan. SEM results showed that the hydrogels had a macroporous structure with interconnected pores inside. CCK-8 results indicated that the hydrogels could significantly reduce the viability of leukocytes. In addition, the hydrogel increased the expression of BCL-2 with increasing dose and is promising to be used as a drug carrier material for leukemia treatment.

Next-CLL, a New Next-Generation Sequencing–Based Method for Assessment of IGHV Gene Mutational Status in Chronic Lymphoid Leukemia

Current guidelines for patients with chronic lymphocytic leukemia (CLL) recommend mutation status determination of the clonotypic IGHV gene before treatment initiation to guide the choice of first-line therapy. Currently, commercially available next-generation sequencing (NGS) solutions have technical constraints, as they necessitate at least a 2×300 bp sequencing, which restricts their use for routine practice. The cost of the commercial kits also represents an important drawback. We present a new method called Next-CLL, a ready-to-use strategy to evaluate IGHV gene mutation status using any NGS device (including 2×150 bp sequencers) in routine diagnostic laboratories. The performance of Next-CLL was validated on genomic DNA and cDNA obtained from 80 patients with CLL at diagnosis. Next-CLL identified a productive clone in 100% of cases, whereas PCR with Sanger sequencing led to a 12.5% failure rate. Next-CLL had 100% concordance with the reference technique for IGHV gene identification and allowed assessment of the IGHV mutation status from the leader sequence, following international guidelines. Comparing a large retrospective series of samples, analyzed by using Sanger sequencing (n=773) or Next-CLL (n = 352), showed no bias in IGHV usage or mutational status, further validating our strategy in the real-life setting. Next-CLL represents a straightforward workflow for IGHV analysis in routine practice to assess clonal architecture and prognosis of patients with CLL.

The Charlson comorbidity index and short-term readmission in patients with heart failure: A retrospective cohort study.

The relationship between the Charlson comorbidity index (CCI) and short-term readmission is as yet unknown. Therefore, we aimed to investigate whether the CCI was independently related to short-term readmission in patients with heart failure (HF) after adjusting for other covariates. From December 2016 to June 2019, 2008 patients who underwent HF were enrolled in the study to determine the relationship between CCI and short-term readmission. Patients with HF were divided into 2 categories based on the predefined CCI (low < 3 and high > =3). The relationships between CCI and short-term readmission were analyzed in multivariable logistic regression models and a 2-piece linear regression model. In the high CCI group, the risk of short-term readmission was higher than that in the low CCI group. A curvilinear association was found between CCI and short-term readmission, with a saturation effect predicted at 2.97. In patients with HF who had CCI scores above 2.97, the risk of short-term readmission increased significantly (OR, 2.66; 95% confidence interval, 1.566-4.537). A high CCI was associated with increased short-term readmission in patients with HF, indicating that the CCI could be useful in estimating the readmission rate and has significant predictive value for clinical outcomes in patients with HF.

Clinico-Hematological Pattern of Haematological Malignancies in Patients Referred for Bone Marrow Examination

Background: Chromosomal translocation is a common cause among hematological malignancies thus. a different diagnostic and treatment approach is required in these cases. Aim: To determine frequencies and clinic-hematological features of different hematological malignancies among patients. Methodology: It was a descriptive cross sectional study. Patients (n=284) with hematological malignancy were enrolled from total 1080 bone marrow biopsies. Detailed history, clinical examination and hematological parameters were recorded at time of presentation. Bone marrow aspiration and trephine biopsy were done as per the clinical indication. Data was evaluated by using SPSS version 23. Chi-square test was applied with p-value of less than 0.05 was considered significant. Results: The study showed the high percentage of hematological malignancies (24%) were observed among enrolled patients with CML being the commonest cancer among them. Practical Implication: This study established the clinic-hematological correlation and provided study based suggestions for better diagnosis and treatment of hematological malignancies while using bone marrow microscopic examination as an important diagnostic tool. Conclusion: It was concluded that acute leukemias were common in younger age whereas chronic leukemias and lymphoproliferative disorders in more advanced ages. Keywords: Hematological Malignancies, Bone Marrow Examination and Diagnosis.

Action Mechanism of Metformin and Its Application in Hematological Malignancy Treatments: A Review.

Hematologic malignancies (HMs) mainly include acute and chronic leukemia, lymphoma, myeloma and other heterogeneous tumors that seriously threaten human life and health. The common effective treatments are radiotherapy, chemotherapy and hematopoietic stem cell transplantation (HSCT), which have limited options and are prone to tumor recurrence and (or) drug resistance. Metformin is the first-line drug for the treatment of type 2 diabetes (T2DM). Recently, studies identified the potential anti-cancer ability of metformin in both T2DM patients and patients that are non-diabetic. The latest epidemiological and preclinical studies suggested a potential benefit of metformin in the prevention and treatment of patients with HM. The mechanism may involve the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway by metformin as well as other AMPK-independent pathways to exert anti-cancer properties. In addition, combining current conventional anti-cancer drugs with metformin may improve the efficacy and reduce adverse drug reactions. Therefore, metformin can also be used as an adjuvant therapeutic agent for HM. This paper highlights the anti-hyperglycemic effects and potential anti-cancer effects of metformin, and also compiles the in vitro and clinical trials of metformin as an anti-cancer and chemosensitizing agent for the treatment of HM. The need for future research on the use of metformin in the treatment of HM is indicated.

Myeloproliferative neoplasms: changes since the WHO 2016 classification

A group of international experts, including haematopathologists, oncologists, and geneticists met on September 2021 in Chicago, IL, USA to update the 2016/17 World Health Organization classification system for haematopoietic tumours. After careful deliberation, the group introduced the new International Consensus Classification (ICC) for Myeloid Neoplasms and Acute Leukaemias. The classification was published in June 2022 (Arber DA, Orazi A, Hasserjian RP, et al. Blood 2022; 140: 1200–1228). This presentation focuses on the ICC-2022 category of chronic myeloid leukaemia (CML), BCR::ABL1 positive and the BCR::ABL1 negative myeloproliferative neoplasms (MPNs): essential thrombocythemia, polycythemia vera, primary myelofibrosis, and MPN, unclassifiable. In CML, ICC recognises three disease phases: chronic (CP), accelerated (AP), and blast (BP) phase. Their definition has been streamlined. For the MPN group, ICC chose to preserve the primary role of bone marrow morphology in disease classification and diagnostics, while also acknowledging the complementary role of genetic markers for establishing clonality, facilitating MPN subtype designation, and disease prognostication. Chronic neutrophilic leukaemia (CNL) can now be diagnosed with a WBC of > 13x 109/L. The diagnosis of chronic eosinophilic leukaemia, NOS, now requires a bone marrow showing dysplastic changes. Reference 1. Thiele J, Kvasnicka HM, Orazi A, et al. The international consensus classification of myeloid neoplasms and acute leukemias: myeloproliferative neoplasms. Am J Hematol 2022; doi: 10.1002/ajh.26751. Epub ahead of print. PMID: 36200127.

225 - Chronic eosinophilic leukemia presenting with hypereosinophilic syndrome

225 - Chronic eosinophilic leukemia presenting with hypereosinophilic syndrome

Eosinophilic myeloid neoplasms: an update

This presentation which addresses changes and updates in eosinophilic disorders, is based on the recently published International Consensus Classification of myeloid neoplasms (Arber DA, Orazi A, Hasserjian RP, et al. Blood 2022; 140: 1200–1228). The previous category of myeloid/lymphoid neoplasm with eosinophilia (M/LN-eo) and a specific gene rearrangement is now changed to M/LN-eo with tyrosine kinase gene fusions to reflect the underlying genetic lesions. Two new members, M/LN-eo with ETV6::ABL1 fusion and M/LN-eo with various FLT3 fusions, have been added to the category; and M/LN-eo with PCM1::JAK2 and its genetic variants ETV6::JAK2 and BCR::JAK2 are recognised as a formal entity from their former provisional status. Our updated understanding of the clinical and molecular genetic features of PDGFRA, PDGFRB and FGFR1 neoplasms is summarised. Bone marrow morphology now constitutes one of the diagnostic criteria of chronic eosinophilic leukaemia, NOS (CEL, NOS), and idiopathic hypereosinophilia/hypereosinophilic syndrome (HE/HES), facilitating the separation of a true myeloid neoplasm with characteristic eosinophilic proliferation from those of unknown etiology and not attributable to a myeloid neoplasm. Reference 1. Tzankov A, Reichard KK, Hasserjian RP, Arber DA, Orazi A, Wang SA. Updates on eosinophilic disorders. Virchows Arch 2022; doi: 10.1007/s00428-022-03423-3. Epub ahead of print. PMID: 36214901.

Retrospective Study of T Cell Leukaemia (Large Granular Lymphocyte Variant) in Dogs Associated with Suspected Immune-Mediated Cytopaenia(s) in the Absence of Peripheral Lymphocytosis.

Canine chronic large granular lymphocyte (LGL) leukaemia is commonly characterised by moderate to marked lymphocytosis but not neutropaenia. In humans, LGL leukaemia is often associated with autoimmune disorders, including immune-mediated cytopaenias (mainly neutropaenia). This presentation is rare in dogs. The aim of this retrospective study was to describe the clinical characteristics, treatments, and outcomes of dogs with chronic LGL leukaemia with suspected immune-mediated cytopaenia. Six dogs with a median age of 4.5 years (range 2-8 years) were included in the study. The most common presenting signs were pyrexia and lethargy. All dogs had severe neutropaenia (median neutrophil count 0.07 × 109/L), three had thrombocytopaenia (median platelet count 66 × 109/L), and one had anaemia (HCT 0.32 L/L). In all dogs, bone marrow cytology revealed infiltration of granular T lymphocytes; PARR analysis confirmed clonality in four, and bone marrow flow cytometry identified CD3+ CD8+ neoplastic cells in two cases. All patients received systemic chemotherapy, and the cytopaenias resolved after 1-19 weeks. Two dogs were euthanised 133 and 322 days after diagnosis, two were lost to follow-up after 224 and 357 days, and two were alive at 546 and 721 days. A subset of LGL leukaemia in dogs is associated with immune-mediated cytopaenia and has a unique clinical presentation.

The association of BTLA gene polymorphisms with non-small lung cancer risk in smokers and never-smokers.

Lung cancer is the predominant cause of death among cancer patients and non-small cell lung cancer (NSCLC) is the most common type. Cigarette smoking is the prevailing risk factor for NSCLC, nevertheless, this cancer is also diagnosed in never-smokers. B and T lymphocyte attenuator (BTLA) belongs to immunological checkpoints which are key regulatory molecules of the immune response. A growing body of evidence highlights the important role of BTLA in cancer. In our previous studies, we showed a significant association between BTLA gene variants and susceptibility to chronic lymphoblastic leukemia and renal cell carcinoma in the Polish population. The present study aimed to analyze the impact of BTLA polymorphic variants on the susceptibility to NSCLC and NSCLC patients' overall survival (OS). Using TaqMan probes we genotyped seven BTLA single-nucleotide polymorphisms (SNPs): rs2705511, rs1982809, rs9288952, rs9288953, rs1844089, rs11921669 and rs2633582 with the use of ViiA 7 Real-Time PCR System. We found that rs1982809 within BTLA is associated with NSCLC risk, where carriers of rs1982809G allele (AG+GG genotypes) were more frequent in patients compared to controls. In subgroup analyses, we also noticed that rs1982809G carriers are significantly overrepresented in never-smokers, but not in smokers compared to controls. Additionally, the global distribution of the haplotypes differed between the never-smokers and smokers, where haplotypes A G G C A, C G A C G, and C G A T G were more frequent in never-smoking patients. Furthermore, the presence rs1982809G (AG+GG genotypes) allele as well as the presence of rs9288953T allele (CT+TT genotypes) increased NSCLC risk in females' patients. After stratification by histological type, we noticed that rs1982809G and rs2705511C carriers were more frequent among adenocarcinoma patients. Moreover, rs1982809G and rs2705511C correlated with the more advanced stages of NSCLC (stage II and III), but not with stage IV. Furthermore, we showed that rs2705511 and rs1982809 significantly modified OS, while rs9288952 tend to be associated with patients' survival. Our results indicate that BTLA polymorphic variants may be considered low penetrating risk factors for NSCLC especially in never-smokers, and in females, and are associated with OS of NSCLC patients.