scholarly journals Evaluation of Secondary Malignancies in Chronic Lymphocytic Leukemia

2018 ◽  
Vol 4 (Supplement 2) ◽  
pp. 205s-205s
Author(s):  
E. Aladag ◽  
M. Okay ◽  
R. Ciftciler ◽  
T. Heziyev ◽  
N. Sayinalp ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Chemotherapeutic Agents ◽  
Lymphocytic Leukemia ◽  
University Hospital ◽  
Secondary Malignancy ◽  
Secondary Malignancies ◽  
Treatment Protocols ◽  
Hospital System ◽  
Increased Risk ◽  
Significant Difference

Background: Chronic lymphocytic leukemia patients have an increased risk of secondary malignancy. Aim: The aim of the current study was to evaluate secondary malignancy in patients with chronic lymphocytic leukemia. Methods: Patients with chronic lymphocytic leukemia were screened and their diagnosis and last visit data, treatment protocols, the existence of secondary malignancy, if present, diagnosis date of secondary malignancy and its treatment were recorded from hospital system retrospectively. Results: One hundred thirty-four patient (134) followed in Hacettepe University Hospital Hematology Department were enrolled. Of 134, 88 (66%) were male and 46 (34%) were female. A total of 32 patients (23.9%) had a secondary malignancy. Of 32 patients, 8 were genito-urinary system (vulva - vagina - ovary - endometrium - prostate and renal) malignancies, 5 were dermatological system malignancies, 3 were thyroid, 2 were breast, 2 were lung, 1 was gastric and 9 were hematologic system malignancies. Mean age of patients with secondary malignancy were 64.2 ± 2.3 years and those without secondary malignancy were 64.1 ± 1.0 years ( P = 0.943). Mean overall survival in patients with secondary malignancy was 110 months and in those without secondary malignancy was 140 months ( P = 0. 531). 17 of the patients with secondary malignancy had a history of chemotherapy. 11 of these patients received chlorambusil-based treatments. Conclusion: Immune deficiency and chemotherapeutic agents used in the management of chronic lymphocytic leukemia are thought to be responsible for the appearance of secondary malignancies. Although there is no significant difference in terms of survival, these patients should be closely followed for secondary malignancies.

scholarly journals Concurrent Squamous Cell Carcinoma and Chronic Lymphocytic Leukemia Presenting as an Enlarging Neck Mass

2019 ◽  
Vol 7 ◽  
pp. 232470961984290
Author(s):  
Prabhjot Bhinder ◽  
Michael Chahin ◽  
Lara Zuberi
Keyword(s):  
Squamous Cell Carcinoma ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Neck Mass ◽  
Lymphocytic Leukemia ◽  
Secondary Malignancies ◽  
Increased Risk ◽  
History Of ◽  
Tonsillar Squamous Cell Carcinoma

Chronic lymphocytic leukemia (CLL) patients are at an increased risk for developing more aggressive lymphomas via Richter’s transformation and of developing secondary malignancies. Despite the known association for secondary cancers, oropharyngeal cancers occur rarely. We present a case of a woman with a history of CLL who presented to our facility via transfer for impending airway compromise. Her initial workup was consistent with CLL; however, biopsies were taken of the neck mass because of its aggressive nature. She was treated with rituximab with good response. Final pathology showed evidence of CLL and tonsillar squamous cell carcinoma (SCC). Direct laryngoscopy and further biopsies yielded a diagnosis of unresectable oropharyngeal SCC. She was to be treated with chemotherapy and radiation for her SCC while holding treatment for CLL. This case demonstrates a rare and unexpected concurrent diagnosis.

Chronic Lymphocytic Leukemia-Associated Chromosomal Abnormalities and Risk of Secondary Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5636-5636
Author(s):  
Shahzad Raza ◽  
Paul J Hampel ◽  
Belal Firwana ◽  
Zhen Wang ◽  
Yasar Shad ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chromosomal Abnormalities ◽  
Lymphocytic Leukemia ◽  
Secondary Malignancy ◽  
Secondary Malignancies ◽  
Skin Cancers ◽  
Increased Risk ◽  
Trisomy 12 ◽  
13Q Deletion ◽  
Melanoma Skin

Abstract Introduction: Incidence of secondary malignant neoplasm in patients with chronic lymphocytic leukemia (CLL) is already established. Genetic predisposition has been considered to be a possible contributory factor for the preponderance of second cancers in this population. In the present study, we examined the frequency, characteristics, and clinical outcomes of secondary malignancies in patients with CLL based on their Interphase fluorescence in situ hybridization (FISH) panel. Methods: We reviewed the medical records of consecutive patients with CLL observed or treated at Ellis Fischel Cancer Center during the period from 2007-2014. We collected demographic data, CLL Rai stage, treatment history, Interphase fluorescence in situ hybridization (FISH) panel results and the presence of a secondary malignancy (skin cancers, solid tumors and hematologic malignancy excluding CLL transformation).Our aim was to investigate the association between secondary malignancy and chromosomal abnormalities and other risk factors using Chi2test for categorical variables and Wilcoxon rank-sum test for continuous variables. Cox proportional hazard models and logistic regression models were used to evaluate risk factors of developing secondary malignancy and overall survival. Results: We identified 142 CLL patients who were either observed (n=62) or had a history of treatment (n=80) for CLL. 67% were male and 33% were female. 85% of patients were Caucasians, 10% African Americans, and 5% other. Familial CLL was present in 6% of cases. 51% of patients were non-smokers. 5% of patients had cancers preceding the diagnosis of CLL (non-melanoma skin cancers=3, melanoma=1, Hodgkin's lymphoma=1, Prostate=2). 28% of patients developed secondary malignancies after the diagnosis of CLL; among them non-melanoma skin cancers were the most common (78%), followed by cutaneous melanoma (9.5%) and papillary thyroid cancer (4.7%). Other malignancies included lung (2.3%), kidney (2.3%), prostate (2.3%) and ocular melanoma (2.3%). 12% patients had aggressive non-melanoma recurrent skin cancers that require multiple treatments along-with systemic therapy for progressive CLL. CLL-FISH panel at diagnosis was available in 98 patients. Among these patients,13q deletion was present in 45%. Within the 13q deletion group, secondary malignancy was noted in 50% during a median follow up of 7 years. All cases of papillary thyroid cancers were also present in 13q deletion. In contrast, 11q deletion was detected in 15% and trisomy 12 in 18% of patients with incidence of secondary malignancy 40% and 10%, respectively. No solid malignancy other than skin was identified in the 11q deletion and trisomy 12 groups. 17p deletion was present in 5% of cases and 60% of 17p deletion cases had secondary cancers (skin 80%). Normal FISH panel was present in 17% cases and 20% of normal FISH had secondary malignancy (solid 10%, skin 10%). The median overall survival time is 6 years for the entire cohort (IRQ: 3-9 years). Secondary malignancy was associated with worse overall survival (OS) (HR=0.57, 95% CI:0.33-0.98, p=0.04) compare to patients who did not have secondary malignancy. The risk of secondary malignancy is increased in patients with advanced age (OR=1.05, 95% CI:1.00-1.10, p=0.04) and in those who were treated with alkylating agent for CLL OR=6.62, 95% CI:2.08-21.03, p=0.001. However, there were no significant difference on risk of developing secondary malignancy based on specific chromosomal FISH result, Rai stage, smoking, family history and gender. Conclusion: Secondary malignancies are frequent in patients with detectable chromosome abnormality on FISH panel. However, the increased risk of secondary malignancy does not correlate with specific cytogenetic abnormality. Non melanoma skin cancers are exceedingly common in CLL patients and carries aggressive couse in progressive CLL patients. Larger studies are required to identify subtype of CLL based on integrated mutational and cytogenetic subgroup that are at increased risk of specific secondary malignancies. Disclosures No relevant conflicts of interest to declare.

scholarly journals PD-1 inhibition in malignant melanoma and lack of clinical response in chronic lymphocytic leukemia in the same patients: a case series

2020 ◽  
Vol 27 (3) ◽  
Author(s):  
I. Landego ◽  
D. Hewitt ◽  
I. Hibbert ◽  
D. Dhaliwal ◽  
W. Pieterse ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Chronic Lymphocytic Leukemia ◽  
Meta Analysis ◽  
Case Series ◽  
Fold Increase ◽  
Lymphocytic Leukemia ◽  
Western World ◽  
Secondary Malignancy ◽  
Increased Risk ◽  
Adult Leukemia

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world. Unfortunately these patients are often immunosuppressed and at increased risk of infection and secondary malignancy. Previous meta-analysis has found that patients with CLL are at a four-fold increase of melanoma compared to the general population. Recent advancements in our understanding of the programmed death (PD) receptor pathway have led to the advent of immunotherapies to target cancer cells. The use of PD-1 inhibitors is now considered first line treatment for BRAF wild-type metastatic melanoma. Interestingly, early pre-clinical data suggest that inhibition of this pathway may also be used in the treatment of CLL, however clinical trials now published were not successful. In this case series we highlight two cases where patients with CLL and concurrent malignant melanoma undergo treatment with PD-1 inhibitors, and were found to have reductions in their WBC counts but these were not sustained. These cases further illustrate that treatment of CLL with PD-1 inhibitors are ineffective treatment alone.

Survival for melanoma patients with pre-existing chronic lymphocytic leukemia.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e19057-e19057
Author(s):  
Eric D. Whitman ◽  
Rami Bustami
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Proportional Hazards ◽  
Cox Model ◽  
Cox Proportional Hazards ◽  
Lymphocytic Leukemia ◽  
Chi Square ◽  
Risk Of Death ◽  
Increased Risk ◽  
Significant Difference

e19057 Background: Recent successes in melanoma drug development have rekindled interest in immunotherapy for melanoma (MM). Patients (pts) with chronic lymphocytic leukemia (CLL), a malignant expansion of B-lymphocytes, have an impaired immune system and not uncommonly develop secondary MM. We hypothesized that MM pts with pre-existing CLL are more likely to die than MM pts without a second malignancy. Methods: Pts were identified in the updated Surveillance Epidemiology and End Results (SEER) (1973-2008) database with MM only (MEL) or with primary CLL and secondary MM (MELpCLL). Time between diagnosis and death or last follow up and other demographic SEER data were recorded. The Chi-Square Test was used to make unadjusted comparisons between group death rates. A Cox proportional hazards regression model, adjusted for patient characteristics, predicted the risk of death by group. Results: 8,294 SEER pts were included (8,115 in MEL, 179 in MELpCLL). With a median follow-up time of 7 years, 2,454 pts (30%) died. There was a significant difference in mortality rates between the groups: MEL 29% / MELpCLL 71%; p<0.001 by Chi-Square. In the multivariate Cox model (Table), MELpCLL pts were significantly more likely to die than MEL pts (HR = 1.22, 95% CI = 1.02-1.46, p = 0.034). Higher risk of death was also significantly associated with older age and male gender (p<0.001) but not MM location (data not shown). MM data like thickness and ulceration were only available in more recent SEER records, precluding survival analysis. Conclusions: MELpCLL pts had a 22% increased risk of death compared to MEL pts in multivariate analysis, consistent with the hypothesis. [Table: see text]

scholarly journals Secondary Malignancies in Chronic Lymphocytic Leukemia: A Single Centre Retrospective Analysis of 514 Cases

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5279-5279 ◽  
Author(s):  
Gianluigi Reda ◽  
Bruno Fattizzo ◽  
Ramona Cassin ◽  
Nicola Orofino ◽  
Elena Flospergher ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Genital Tract ◽  
Hematological Malignancies ◽  
Lymphocytic Leukemia ◽  
Secondary Malignancy ◽  
Secondary Malignancies ◽  
Secondary Cancers ◽  
Skin Cancers ◽  
Enteric Tract

Abstract Background: chronic lymphocytic leukemia (CLL) is characterized by progressive immunodeficiency with high prevalence of infections, autoimmune phenomena and secondary malignancies. The immune deregulation may be due to the disease itself or it may be a consequence of the treatment performed. Despite the use of highly effective chemo-immunotherapy, CLL remains incurable nowadays, even if the availability of new drugs is improving life expectancy. Aims: to evaluate the incidence of second cancers in CLL patients, and to investigate their relationship with disease features and therapy lines. Methods: 514 CLL patients diagnosed and followed from 1983 until 2014 at our Institution were retrospectively evaluated. Secondary cancers were categorized according to the originating organ or tissue; skin cancers were divided into melanoma and non-melanoma. History of neoplasia preceding CLL diagnosis was also registered. Results: clinical, hematological and biological characteristics at CLL diagnosis are listed in Table 1. During the follow up 88 patients (17%) developed secondary cancers, with a mean time from diagnosis to secondary neoplasia of 9 years. Considering tumor site, we observed 9 hematological malignancies, 9 lung, 5 breast, 19 uro-genital tract (5 kidney, 10 prostate, 4 bladder, 2 uterus, and 2 ovarian), 15 gastro-enteric tract (12 colon, 2 gastric and 1 tongue), 4 pancreas, 3 melanoma and 15 skin cancers other than melanoma. No significant differences were observed according to age, gender, Rai/Binet stage and hematologic parameters in patients with or without secondary tumors (Table 1). Considering prognostic features, no association was found with 13q deletion, chromosome 12 trisomy, VHIG mutational status, or with ZAP-70 and CD-38 positivity. On the contrary, the development of second cancers was associated with the presence of chromosome 17p (8% with secondary neoplasia versus 6% without, p=0.05) and 11q deletions (13% versus 9%, p=0.08). Medical history was positive for malignancies in 70 patients (13%): 2 hematological malignancies, 3 airways (2 lower and 1 upper), 3 breast, 6 uro-genital tract (3 bladder, 3 prostate, 2 uterus and 1 ovarian), 3 gastro-enteric tract, 3 skin cancers other than melanoma, and 3 melanoma. As regards treatment, 46/88 (52.3%) and 219/426 (51.4%) patients with or without secondary cancers, underwent at least one therapy line. Eighty-six patients were treated with fludarabine containing regimens, of whom 11 developed a secondary cancer; 180 patients received chlorambucil and 34 developed a secondary tumor. Among 65 patients who underwent alemtuzumab treatment, 10 were later diagnosed with a second cancer. During the follow up, 121 patients died, 18 with secondary malignancy. Of note, 41 patients died from CLL progression, 2 from thrombotic events, 11 from infections and 8 from secondary malignancy. Conclusions: secondary malignancies are not infrequent in patients with CLL and their occurrence is not clearly related to biologic markers or to the treatment performed. A careful clinical follow up, encompassing sex and age adjusted tumors screening, is advisable for an early diagnosis and appropriate treatment of secondary malignancies in CLL. Table 1. clinical and laboratory features of 514 CLL patients with or without secondary malignancies. Data are expressed as median (range) or absolute number (%). Secondary malignancies Yes (N=88) No (N=426) Age years 64 (39-80) 63 (31-90) Gender M/F 57/31 250/176 Follow-up years 12 (0-30) 12 (1-25) Rai/Binet<C/III> C/III 85 (97) 3 (3) 401 (94) 25 (6) WBC x10e3/mmc 18.74 (3.6-138) 17.3 (3-384) ALC x10e3/mmc 12.63 (1.8-91.8) 11.9 (1.4-381) Hb g/dL 14 (9-17) 14 (8-18) PLT x10e3/mmc 198 (77-608) 184 (58-472) LDH U/L 325 (144-838) 334 (142-795) Beta2microglobulin mg/L 2 (1-23) 2 (0-10) FISH*Del11qDel13qDel17p+12 6 (13) 19 (40) 4 (8) 6 (13) 23 (9) 101 (40) 15 (6) 38 (15) VHIG unmutated** 15 (42) 80 (39) ZAP-70 positive*** 14 (39) 73 (36) CD-38 positive**** 15 (42) 76 (37) *Tested in 48 and 252 patients respectively. **Tested in 36 and 205 patients respectively. ***Tested in 33 and 182 patients respectively. ****Tested in 56 and 291 patients respectively. Disclosures No relevant conflicts of interest to declare.

scholarly journals EXPRESSION OF micro RNAs (miRNAs) IN MYELODYSPLASTIC SYNDROME (MDS)

2019 ◽  
Vol 141 (7-8) ◽  
pp. 226-232
Keyword(s):  
Gene Expression ◽  
Myelodysplastic Syndrome ◽  
Healthy Volunteers ◽  
Myelogenous Leukemia ◽  
University Hospital ◽  
Gene Expressions ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Micro Rnas ◽  
Significant Difference

Myelodisplasia or myelodysplastic syndrome (MDS) is the name for a group of heterogeneous clonal hematological disorders of hematopoietic stem cells followed by ineffective hematopoesis of one or more cell lines and the emergence of consequent cytopenias with increased risk of progression to acute myelogenous leukemia (AML). Micro Messenger Ribonucleic Acids (miRNAs) are short, non-coding RNA molecules that, apart from contributing to MDS pathogenesis, act as regulators of epigenetic mechanisms and also are recognized as potential prognostic markers for early diagnosis and classification of MDS. The aim of the study was to examine the levels of gene expression of specific miRNAs (hsa-miR-125a, hsa-miR-99b, hsa-miR-126 and hsa-miR-125b) in healthy volunteers plasma and MDS diagnosed patients. Gene expressions of miRNAs were determined at the Clinical Institute of Medical Biochemistry and Laboratory Medicine, Merkur University Hospital, accredited according to EN ISO 15189:2012, in plasma samples of four healthy volunteers and 33 MDS patients diagnosed at the Institute of Hematology of the Clinic for Internal Diseases of Merkur University Hospital, Reference Center of the Ministry of Health of the Republic of Croatia for Diagnosis and Treatment of MDS. Statistically significant difference in gene expression of miRNA in healthy volunteers compared to the MDS patients was not found (P [hsa-miR-125a] = 0.398; P [hsa-miR-99b] = 0.134; P [hsa- miR-126] = 0.305; P [hsa-miR-125b] = 0.079). MiRNA ratios of hsa-miR-125a and hsa-miR-99b in MDS patients were almost twice as high compared to normalized levels of gene expression in healthy volunteers (2.30 versus 1.90), and the level of change of miRNAs hsa-miR-125 and hsa-miR-99b was more than two times higher than the level of change of miRNA hsa-miR-125b. Finally, the results of the research indicate that the gene expression of miRNAs hsa-miR-125a and hsa-miR-99b could be regulated by the same mechanism and could be clinically relevant in MDS patients.

scholarly journals Could the candidate causal gene (LZTFL1) identified by Oxford University scientists, which doubles the risk of COVID-19-related respiratory failure, be used to boost the Weak immunogenicity of COVID-19 mRNA vaccines in patients with B-cell chronic lymphocytic leukemia (CLL)???. A double edged sward

2021 ◽  
Author(s):  
Mahmoud Ramadan Elkazzaz ◽  
Yousry Esam-Eldin Abo-Amer ◽  
Amr Ahmed ◽  
Tamer Haydara
Keyword(s):  
Respiratory Failure ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Risk Allele ◽  
Lymphocytic Leukemia ◽  
Causal Gene ◽  
Oxford University ◽  
Increased Risk ◽  
University Scientists ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Patients with B-cell chronic lymphocytic leukemia (CLL) have an increased risk of severe infections due to disease- and treatment-related immunodeficiency. As a result, patients with hematologic malignancies have been given priority for primary COVID-19 vaccination. Unfortunately, many studies have suggested that patients with B-cell chronic lymphocytic leukemia (CLL) who have been fully vaccinated can develop severe and often fatal complications. Therefore, adjuvants that can induce mRNA vaccine efficacy are desperately needed for this category of patients with haematological malignancies. A recent, study by Oxford University scientists showed that leucine zipper transcription factor-like 1(LZTFL1), as a candidate causal gene and its enhancer the rs17713054 A risk allele was significantly responsible for the twofold increased risk of respiratory failure from COVID-19 associated with 3p21.31.By using sequence analysis, the risk allele generates a second CCAAT/enhancer binding protein beta (CEBPB) motif in the enhancer. Moreover, neither LZTFL1 variants found in T cells nor B cells are responsible for increasing death risk from COVID-19 infection according to oxford study. Here, we propose attestable hypothesis that trans retinoic acid could enhance the immune response in vaccinated patients with B-cell chronic lymphocytic leukemia (CLL) according to the recent findings of Oxford scientists by inducing the casual gene(LZTFL1) in CD4 T cells and inhibiting (CEBPB) motif.

scholarly journals Challenges in Steroid and Anticoagulant Therapy in Severe COVID-19 Pneumonia: A Prospective Study

Antibiotics ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1214
Author(s):  
Alaa Thabet Hassan ◽  
Alaa E. Abd Elmoniem ◽  
Marwa Mahmoud Abdelrady ◽  
Mona Embarek Mohamed ◽  
Mohamed A. Mokhtar ◽  
...  
Keyword(s):  
Treatment Protocol ◽  
Severe Pneumonia ◽  
High Risk Group ◽  
University Hospital ◽  
Treatment Protocols ◽  
Neutrophil Lymphocyte Ratio ◽  
Treatment Type ◽  
Acute Kidney Disease ◽  
Significant Difference ◽  
Group B

Background: As COVID-19 has neither a standard treatment protocol nor guidelines, there are many treatment protocols for anti-inflammatory corticosteroids and anti-coagulations for severe COVID-19 pneumonia patients. This study aimed to assess the most suitable modality in this high-risk group. Methods: A prospective, experimental study design was adopted that included 123 severe COVID-19 pneumonia patients admitted at Assiut University Hospital. Patients were divided into three groups according to a combined corticosteroid and anticoagulants therapy protocol. Group A included 32 patients, group B included 45 patients, and group C included 46 patients. Assessment of cases was conducted according to the treatment type and duration, weaning duration from oxygen therapy, length of hospital and ICU stay, and complications during treatment. Three months follow-up after discharge was performed. Results: the three patient groups showed significant differences regarding the 3-month outcome, whereas Group C showed the highest cure rate, lowest lung fibrosis, and lowest mortality rate over the other two groups. The in-hospital outcome, the development of pulmonary embolism, bleeding, hematoma, acute kidney disease, and myocardial infarction showed a significant difference between groups (p values < 0.05). Mortality predictors among severe COVID-19 patients by multivariable Cox hazard regression included treatment modality, history of comorbid diseases, increased C reactive protein, high neutrophil-lymphocyte ratio, and shorter ICU and hospital stay. Conclusion: the use of combined methylprednisolone and therapeutic Enoxaparin, according to a flexible protocol for COVID-19 patients with severe pneumonia, had two benefits; the prevention of disease complications and improved clinical outcome.

scholarly journals Total Proteome Analysis Identifies Migration Defects As a Major Pathogenetic Factor in IGHV-Unmutated Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 718-718 ◽  
Author(s):  
Gina L Eagle ◽  
Rosalind E Jenkins ◽  
Kathleen J Till ◽  
Jithesh Puthen ◽  
Ke Lin ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Computational Analysis ◽  
Lymphocytic Leukemia ◽  
Differentially Expressed ◽  
Differentially Expressed Proteins ◽  
Data Set ◽  
Clinical Behaviour ◽  
Mutational Status ◽  
Significant Difference ◽  
Total Proteome

Abstract The mutational status of the immunoglobulin heavy chain variable region (IGHV) defines two clinically distinct forms of chronic lymphocytic leukemia (CLL) known as mutated (M-CLL) and un-mutated (UM-CLL). Patients with M-CLL usually have a favourable outcome whereas those with UM-CLL develop progressive disease and have shorter survival. However, the molecular mechanisms responsible for the more aggressive clinical behaviour associated with UM-CLL are not well understood. Here we describe the application of isobaric tags for relative and absolute quantification (iTRAQ) based mass spectrometry (MS) to analyse the total proteome of M-CLL and UM-CLL samples. This has enabled us to generate the largest quantity of proteomic information for CLL to date and, in particular, to directly compare the functions of differentially expressed proteins between UM-CLL and M-CLL cells through a systems biology approach. We isolated CLL cells from the peripheral blood from 18 CLL patients (9 UM-CLL, 9 M-CLL) and prepared cellular protein extracts which were digested and subjected to labelling with iTRAQ reagents, as previously described (Kitteringham et al, J Proteomics, 2010;73(8):1612-1631). Principal component analysis was used to assess variance across the data set generated by iTRAQ-MS. Statistical significance of the difference in the levels of expression of proteins between UM-CLL and M-CLL samples was determined using student T-test (2-tailed). Several differentially expressed proteins identified by iTRAQ-MS were also validated by immunoblotting. Computational analysis was performed to examine the functions of the differentially expressed proteins and their associated signalling pathways using the GeneGo pathway maps in the Metacore™ database (Thomson Reuters, NY, USA). Unsupervised clustering, based on the expression of 3521 identified proteins, separated CLL samples into two groups corresponding to IGHV mutational status. We identified 274 proteins that were differentially expressed between UM-CLL and M-CLL subgroups (p<0.05, Figure 1A). Hierarchical clustering based on the relative expression of differentially expressed proteins also separated individual CLL cases into two distinct clusters according to their IGHV status (Figure 1B). Computational analysis showed that 43 cell migration/adhesion pathways were significantly enriched (p<0.05) by 39 differentially expressed proteins, 35 of which were expressed at significantly lower levels in UM-CLL samples. Furthermore, UM-CLL cells under-expressed proteins associated with cytoskeletal remodelling and over-expressed proteins associated with transcriptional and translational activity. Taken together, these findings indicated that UM-CLL cells are less migratory and more adhesive than M-CLL cells, resulting in their retention in lymph nodes where they are exposed to proliferative stimuli. In agreement with this hypothesis, analysis of an extended cohort of 120 CLL patients revealed that twice as many patients with UM-CLL than M-CLL had documented lymphadenopathy (50% v 24%; P<0.01). The association between UM-CLL and lymphadenopathy was not simply a reflection of increased tumour burden as there was no significant difference in the leukocyte count between the two groups (medians of 37 x 109/L and 28 x 109/L, respectively; P>0.05). In addition, other pathways that promote cell survival and proliferation in UM-CLL cells were also enriched by the differentially expressed proteins. These include the immune response pathway involving B-cell receptor (BCR) signalling (P=0.006), the endoplasmic reticulum (ER) stress response pathway (P=0.035) and the Wnt signalling pathway (P=0.006). Our study has shown that quantitative analysis of the total proteome by iTRAQ-MS was able to separate individual CLL cases according to IGHV status and explained the more aggressive clinical behaviour of UM-CLL and its particular sensitivity to novel therapeutic agents that induce anatomical displacement from the lymph node microenvironment, such as ibrutinib and idelalisib. Moreover, in keeping with the ability of proteomics to detect alterations in gene expression resulting from both transcriptional and post-transcriptional mechanisms, the study illustrates the considerable potential of iTRAQ-MS coupled with computational analysis to elucidate pathogenetic mechanisms and indicate therapeutic strategies in cancer. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Prognostic Significance of PET/CT in Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Frontline Chemoimmunotherapy

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1773 ◽  
Author(s):  
Marika Porrazzo ◽  
Emanuele Nicolai ◽  
Mara Riminucci ◽  
Candida Vitale ◽  
Marta Coscia ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Chronic Lymphocytic Leukemia ◽  
Negative Impact ◽  
Prognostic Significance ◽  
Lymphocytic Leukemia ◽  
Independent Effect ◽  
Proliferating Cells ◽  
Richter Syndrome ◽  
Increased Risk ◽  
Pet Ct

The role of positron emission tomography/computed tomography (PET/CT) in identifying Richter Syndrome (RS) is well established, while its impact on the survival of patients with chronic lymphocytic leukemia (CLL) has been less explored. The clinical characteristics and PET/CT data of 40 patients with a biopsy-proven CLL who required frontline chemoimmunotherapy, FCR (fludarabine, cyclophosphamide, rituximab) in 20 patients, BR (bendamustine, rituximab) in 20, were retrospectively analyzed. Standardized uptake volume (SUVmax) values ≥ 5 were observed more frequently in patients with deletion 11q (p = 0.006) and biopsies characterized by a rate of Ki67 positive cells ≥ 30% (p = 0.02). In the multivariate analysis, the presence of large and confluent PCs emerged as the only factor with a negative impact on progression-free survival (PFS), and overall survival (OS). Deletion 11q also revealed a significant and independent effect on PFS. SUVmax values ≥ 5 showed no statistical impact on PFS while in multivariate analysis, they revealed a significant adverse impact on OS (median survival probability not reached vs. 56 months; p = 0.002). Moreover, patients with higher SUVmax values more frequently developed Richter Syndrome (p = 0.015). Our results show that higher SUVmax values identify CLL patients with a pronounced rate of proliferating cells in the lymph-node compartment, inferior survival, and an increased risk of developing RS.

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