scholarly journals A Patient with Chronic Lymphocytic Leukemia and Bone Localization: A Case Report

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5301-5301
Author(s):  
Iolanda Donatella Vincelli ◽  
Patrizia Cufari ◽  
Said al Sayyad ◽  
Carmelo Tuscano ◽  
Natale Porta ◽  
...  

Abstract Metastatic disease of the bone is a rare complication of chronic lymphocytic leukemia (CLL), it may be result from richter's transformation or metastatic from non lymphoid malignancies. CLL is the most common form of adult leukemia, with the median age of 70 years at diagnosis [Siegel et al. 2013]. The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B-lymphocytes.The result is the increased number of lymphocytes in the peripheral blood, leukocytosis with absolute lymphocytosis, the increase of the lymphnodes, the increase in size of the spleen. The diagnosis of chronic lymphocytic leukemia B requires the presence of Clonal B cells in the peripheral blood at or above 5,000 / ul for at least 3 months. Typing immunophenotypical pathological lymphocytes are positive for surface antigens CD5, CD19, CD23, weakly positive for CD20 and CD22, generally negative FMC7 and CD79b; also expressing surface immunoglobulins. The Rai and Binet staging systems, which are established by physical examination and blood counts, have been recognized as standards for deciding whether to begin treatment. Patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. For fit patients, chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab represents the current standard therapy. For unfit patients, treatment with an anti-CD20 antibody (obinutuzumab, rituximab, ofatumumab) plus a milder chemotherapy (Chlorambucil) may be applied. At relapse, if the treatment-free interval exceeds two to three years, the initial treatment may be repeated, if the disease relapses earlier, drugs such as bendamustine (plus rituximab), alemtuzumab, lenalidomide, ofatumumab, ibrutinib, or idelalisib, must be choosen. Patients with a del(17p) or TP53 mutation can be treated with ibrutinib or a combination of idelalisib and rituximab. in relapsing patients with TP53 mutations or del(17p) or patients that are refractory to repeated chemoimmunotherapies, an allogeneic SCT may be considered [Hallek M 2015]. In this article we show a case of a 66-year-old man with CLL and a bone localization. In 2011 diagnosis of CLL, Rai Stage 0, Binet Stage A. Principal characteristics at diagnosis: HB 13.2 g /dl, White Blood Cells 15.800 / mm3, lymphocytes 61%, neutrophils 32%, monocytes 4%, platelets 141.000/mm3; normal hepatic end renal function; flowcytometric immunophenotyping of the peripheral blood revealed B-cell CLL; prognostic factors: CD38 negative, ZAP70 positive, rearrangement of the immunoglobulins mutated; FISH: negative; CT chest / abdomen / pelvis: presence of multiple aorto-pulmonary and axillary adenopathies (max diameter of 2 centimeters); bone marrow biopsy: infiltration of CLL equal to 60% of global cellularity. The patient was only observed until January 2015, when he was hospitalized due to acute anemia, requiring supportive therapy, and right foot pain . So it was decided to re-evaluate the whole disease in order to decide whether to start chemotherapy. The disease was staged again with instrumental and laboratory tests: presence of renal insufficiency, egd and colonoscopy negative, Coombs' test negative, bone marrow biopsy confirmed the diagnosis of chronic lymphocytic with bone marrow infiltration of 90%, abdomen ultrasound showed only moderate splenomegaly. On February, persistence of right foot pain and appearance of swelling, assessed by the orthopedic as a suspected algic and dystrophic syndrome. So he suggested to perform scintigraphy which revealed: pronounced inflammatory osteometabolic reaction of the right tibia/fibula/ankle third distal which could be referred, in the first evaluation, to algic and dystrophic syndrome. However, a local biopsy was performed: localization of chronic lymphocytic leukemia. On March 2015 a total body TC showed 2 nodular calcifications in the right lung lobe, multiple right paratracheal, barety space, aortopulmonary and axillary adenopathies. Prostate size increased. In order to study carefully the liver and prostate lesions, an ultrasound abdomen was performed that documented only enlarged spleen, normal size liver, free of focal disease, increased prostate due to symmetric bilobate hypertrophy . After the second cycle of chemotherapy, prolonged thrombocytopenia, so he continues only with a radiotherapy program. Disclosures No relevant conflicts of interest to declare.

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3866-3866
Author(s):  
Payal Gupta ◽  
Amit K. Mittal ◽  
Dennis D Weisenburger ◽  
Philip Bierman ◽  
Shantaram S Joshi

Abstract Abstract 3866 Chronic Lymphocytic Leukemia (CLL) is a monoclonal B-cell disorder with accumulation of leukemic cells in peripheral blood, bone marrow and lymphoid organs. It presents with a heterogeneous clinical course. Many patients survive long periods of time without any need for treatment, whereas other patients show resistance to treatment or relapse soon after administration of therapy. Although some prognostic markers such as mutational status of immunoglobulin variable heavy chain, chromosomal abnormalities, CD38 levels, or ZAP-70 expression may help predict at initial diagnosis which patients will have more aggressive disease, the exact factors that can determine chances of remission in CLL are still not clear, making treatment challenging. Furthermore, CLL remains an incurable disease, necessitating a way for controlling its progression. Identifying novel molecular signatures associated with refractory CLL disease may help devise targeted treatment strategies and thus may prolong survival times and prevent the progression of CLL in relapsed patients. Considering this, we performed gene expression profiling (GEP) on peripheral blood (PB), bone marrow (BM) and lymph node (LN) samples collected at the time of diagnosis. We divided CLL samples into 3 groups based on their response to treatment; i) Stable CLL group: asymptomatic patients requiring no treatment, ii) Treated but stable CLL group: patients required treatment but had stable disease for at least one year after the end of the treatment cycle, and iii) Relapsed CLL: patients who relapsed within a year of end of the treatment cycle. Significance analysis of microarray (SAM) revealed that the heat-shock protein (HSP) signature (HSJ2, HSP70, HSP90, HSP60, HSP10, HSP 105, HSP40, HSP27, HSPA2, HSJ1, HSF4, HSPCA), BCR signaling pathway (JUN, NFATC4, NFKBIE, PPP3CB, TRAF3, CD81, CCT4), activation markers (CD81, CD83) and MMPs (MMP3, MMP9) were overexpressed in relapsed PB-CLL (n=3) compared to stable PB-CLL (n=6) and treated but stable PB-CLL (n=10). Overexpression of heat-shock protein signature genes were further observed in additional relapsed PB-CLL (n=6) group compared to other two PB-CLL (n=22) group. Interestingly, the HSP signature was consistently overexpressed in relapsed BM-CLL (n=6) and LN-CLL (n=12) compared to stable and treated but stable BM-CLL (n=11) and LN-CLL (n=3) groups. HSPs are considered chaperones of tumorigenesis and known to enhance survival, migration, and proliferation of tumor cells which may contribute to relapse in patients. Furthermore, the HSPs genes (HSP90 and HSP70) were significantly overexpressed in LN-CLL as compared to PB-CLL which implies important role of the microenviroment in rendering CLL refractory. To investigate the link between the expression of the individual genes with the aggressiveness of the disease, Kaplan-Meier log-rank tests were performed. We found that the higher expression of HSP90A, HSP90B, HSJ, and MMP9 were significantly (p<0.05) associated with shorter time to treatment. In summary, our study suggests that HSP genes are overexpressed in refractory CLL patients and thus are promising targets to improve clinical outcome. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 37-37
Author(s):  
Iolanda Donatella Vincelli ◽  
Patrizia Cufari ◽  
Carmelo Toscano ◽  
Al Sayyad Said ◽  
Mauro Campello ◽  
...  

Chronic lymphocytic leukemia (CLL) is an indolent lymphoproliferative disorder and is manifested by progressive accumulation of B cells in the blood, bone marrow and lymphatic tissues. Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disorder characterized by the presence of all the stages of myeloid development in the peripheral blood, and it is believed to be driven by the aberrant protein tyrosine kinase, a product of the mutant BCR-ABL1 gene.Multiple Myeloma (MM) is characterized by the accumulation of clonal plasmcells in the bone marrow with skeletal lesions, anemia, hypercalcemia and renal failure. Our patient is a 78 year-old man. In 2014 diagnosis of CLL and monoclonal gammopathy of undetermined significance (MGUS).At diagnosis: HB 13.5 g/dl; normal renal function;calcium 8.7 mg/dl;IgG 1678 mg/dl,serum immunoelectrophoresis: IgG kappa, Bence Jones kappa; total protein 7.5 g/dl, beta1 6,5%, beta2 24,1%;peripheral blood immunophenotyping showed CLL, FISH:negative;Cariotype: 46, XY; RX skeleton: positive for osteolytic lesions, total body TC scan: adenopathies of 18 mm and 15 mm at bilateral axillary level, norma spleen, adenopathy of 22 cm in the left obturator iliac region; presence of left hip prosthesis; bone marrow biopsy: localization by low-grade plasmacytoma.No CLL.The patient was only observed until April 2015, when there was a presence of myelocytes and metamyelocytes in peripheral blood and an increased spleen (18 cm). So he performed : bone marrow aspirate: diagnosis of CML (Sokal Score: 1,34 H; Eutos Score: 60 L, Hasford Score 1488,5);bone marrow biopsy: suggestive for a myeloproliferative disease (CML), MGUS with a modest lymphoid B component,BCR-ABL: 60;FISH: pathological presence of double fusion signal of the ABL1 and BCR loci in 209 of 271 interphase nuclei examined (77%).The patient started therapy with Imatinib, 400mg/die until July 2015, on the basis of the good response to treatment and the progressive increase of the M component that confirmed the progression to MM: Hb 9.1 g/dL, creatinine 1,1 mg/dl;calcium 10,5 mg/dl;total protein: 8,6 g/dl, gamma 48.02% (CM 4 gr); IgG 3536 mg/dl, cariotype: male with t (9; 22) and Philadelphia chromosome (25%);BCR-ABL: 14,32; bone marrow aspirate: plasmacells 15%;bone marrow biopsy: intermediate-interstitial plasmacytoma, CLL / lymphoma; RMN whole body: hyperintensity at the level of the seventh right rib; PET: osteolytic lesions of the side arch tenth right rib, right iliac bone, left iliac region, right tibia third diaphyseal.RX right hemithorax: osteolytic area at the level of the seventh right rib. So the patient started treatment with Bortezomib, Desamethasone, Alkeran (total 7 cycles).On March 2016, he performed a radiography that showed many osteolytic areas of 45 mm on third distal femur, third proximal and intermediate tibia, third proximal and third distal of fibula.A second PET documented a further MM progression due to new bone localizations and a left tibia biopsy showed localization disease. Radiotherapy colleagues have ruled out the usefulness of a radiation therapy program in consideration of the cerebral damage risk. On June 2016 the patient started a treatment with Lenalidomide for 15 days, interspersed by Glivec, maintaining the disease stable. In September 2017 he developed diplopia and with a nasal surgery, only inflammatory tissue was exported. A revision of the material confirmed plasmacytoma localization. In the same period appearance of a right gluteus sore treated initially with surgical dressing.As blood tests revealed increase of paraprotein levels, bone marrow biopsy resulted negative to myeloma and lymphoma diseases, instead a gluteal skin biopsy revealed plasmacytoma. It was decided to treat cerebral localization due to diplopia and peripherical paralysis. Radiotherapy was started on April 2018 (18 sessions). Bone marrow aspirate test showed plasmacells 15%, BCR-ABL dosage: 213,87, M component increase(5gr), IgG 4440 mg/dl, creatinine and serum calcium: normal. Due to disease progression, a rescue chemotherapy was started according to PAD protocol. After 4 cycles, a bone marrow aspirate documented the presence of plasmacells equal to 80%.The cytogenetic study confirmed the presence of a complex karyotype. So the patient started therapy with Daratumumab, Lenalidomide and Desamethasone which is currently ongoing with an excellent hematological and clinical response Disclosures Ciolli: Janssen: Honoraria; Abbvie: Research Funding.


2000 ◽  
Vol 124 (9) ◽  
pp. 1361-1363
Author(s):  
Anwarul Islam ◽  
Adrian O. Vladutiu ◽  
Theresa Donahue ◽  
Selina Akhter ◽  
Amy M. Sands ◽  
...  

Abstract The expression of CD8, a restricted T-cell antigen, on B cells in B chronic lymphocytic leukemia is rare, and its significance, if any, remains unknown. We report herein a patient with B chronic lymphocytic leukemia in whom CD8 was strongly expressed on all B cells, both in the bone marrow and peripheral blood. The patient required no therapy for 6 years after being diagnosed as having B chronic lymphocytic leukemia. Then, when the disease progressed, he was treated with conventional doses of fludarabine phosphate (25 mg/m2 daily for 5 days), but unlike other patients with B chronic lymphocytic leukemia he tolerated this therapy poorly. He received a total of only 4 series of fludarabine therapy, and following each course of treatment, he developed considerable myelosuppression. After the fourth course of therapy, his bone marrow failed to show any evidence of regeneration, and he died as a result of intercurrent respiratory tract infection 1 month after his last dose of fludarabine was given.


Blood ◽  
1978 ◽  
Vol 52 (1) ◽  
pp. 255-260 ◽  
Author(s):  
R Hoffman ◽  
S Kopel ◽  
SD Hsu ◽  
N Dainiak ◽  
ED Zanjani

Abstract The pathogenesis of the anemia associated with malignancy was investigated in a patient with T cell chronic lymphocytic leukemia. The plasma clot culture system was used as a measure in vitro of erythropoiesis. The patient's peripheral blood and marrow T lymphocytes obtained both before and after transfusion therapy suppressed erythroid colony formation by normal human bone marrow cells. Pretreatment of the patient's bone marrow T cells by antithymocyte globulin (ATG) and complement reversed this suppression. In addition, pretreatment of the patient's marrow cells with ATG and complement markedly augmented erythropoiesis in vitro. The expression of erythroid activity caused by the selective destruction of the suppressor T lymphocytes in the patient's bone marrow with ATG and the suppression of normal erythropoiesis by the patient's bone marrow and peripheral blood lymphocytes suggest that interaction between the malignant T cell and the erythropoietin-responsive stem cell is important in production of anemia in this patient.


2015 ◽  
Vol 134 (4) ◽  
pp. 255-262 ◽  
Author(s):  
Maciej Grzywnowicz ◽  
Agnieszka Karczmarczyk ◽  
Katarzyna Skorka ◽  
Malgorzata Zajac ◽  
Joanna Zaleska ◽  
...  

Background: The programmed death 1 (PD-1) receptor pathway is responsible for the negative regulation of both T and B lymphocytes upon activation of these cells. There is growing evidence that chronic lymphocytic leukemia (CLL) cells exploit the PD-1 ligand (PD-L1) to resist antitumor immune reactions and maintain their survival by shaping their own microenvironment. Methods: We used a quantitative RT-PCR method to analyze PD-L1 gene expression in bone marrow and peripheral blood mononuclear cells, representing the proliferation and accumulation compartments of CLL. Results: PD-L1 expression was found to be significantly higher in 112 CLL patients than in controls. Levels of PD-L1 expression in bone marrow and peripheral blood were comparable and showed a positive correlation. Furthermore, expression of PD-L1 strongly correlated with expression of PD-1 receptor in mononuclear cells from the same compartment, and was not affected by incubation with immunomodulatory drug thalidomide. Conclusion: PD-L1 expression is shared between CLL cells localized in distinct disease compartments, demonstrating that PD-1/PD-L1 a universal target for therapy.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1372-1372
Author(s):  
Hendrik W. Van Deventer ◽  
Robert Mango ◽  
Jonathan Serody

Abstract Abstract 1372 Background: Chemotherapy resistance in chronic lymphocytic leukemia (CLL) can be mediated by anti-apoptotic signals produced by stromal or nurse-like cells. Developing strategies to overcome this resistance is hindered by the lack of suitable “stromal” targets responsible for these signals. We have discovered that erythroid differentiation regulator 1 (ERDR1) may be a candidate target for such a strategy. In this study, we show Erdr1 is generated by several stromal cell types including bone marrow stromal cells, fibrocytes, and nurse-like cells. Furthermore, inhibition of stroma-generated Erdr1 results in increased apoptosis of co-cultured CLL cells. Methods/Results: We initially identified Erdr1 on an Affymetrix array that compared the gene expression of wild type and CCR5-/- mice with pulmonary metastasis. The increased expression of Erdr1 in the wild type mice was particularly pronounced in the pulmonary mesenchymal cells. Therefore, these cells were transfected with one of two shRNAs (shRNA #9 or shRNA#11) and the survival of these cells was compared with mesenchymal cells transfected with a non-targeted control vector. After 15 days in culture, the control cells expanded normally; however, no significant expansion was seen in either the shRNA#9 or shRNA#11 transfected cells. These differences in cellular expansion were associated with differences in apoptosis. 21.4+1.6% of the Erdr1 knockdown cells were annexin V+ compared to 11.2+1.9% of the non-targeted control (p<0.03). Using GFP as a marker for transfection, we were also able to show that knockdown of Erdr1 increased the apoptosis of surrounding non-transfected mesenchymal cells. Thus, Erdr1 is a critical protein for the survival of stromal cells. Further analysis of the mesenchymal cell subpopulations revealed the greatest expression of Erdr1 in the CD45+, thy1.1+/− fibrocytes. When compared to CD45- fibroblasts, the fibrocytes expressed CCR5 and increased Erdr1 expression by 14.2+/−2.9 fold when treated with the CCR5 ligand CCL4. Given the similarities between fibrocytes and nurse-like cells, we went on to measure the effect of Erdr1 inhibition on CLL cells. In these experiments, stable Erdr1 knockdown and control clones were selected after the transfection of the bone marrow stromal cell line M2-10B4. These clones were then co-cultured with primary CLL cells. At 96 hours, leukemia cells co-cultured with the control lines had expanded by 1.33 + 0.9 compared to 0.74 + 0.22 fold in the knock-down lines (p<0.03). As before, the lack of cellular expansion was associated with an increase in apoptosis. To further show the relevance of these findings to CLL, we demonstrated that human fibrocytes and nurse-like cells expressed mRNA and protein for ERDR1 in all patient samples tested. Implications for the treatment of human disease: Our data demonstrate that ERDR1 is a critically important protein for the survival of nurse-like cells. These data suggest that targeting ERDR1 or the upstream pathway through CCR5 might be a novel approach for the treatment of CLL. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3895-3895
Author(s):  
Yair Herishanu ◽  
Inbal Hazan-Hallevi ◽  
Sigi Kay ◽  
Varda Deutsch ◽  
Aaron Polliack ◽  
...  

Abstract Abstract 3895 Chronic lymphocytic leukemia (CLL) cells depend on their microenvironment for proliferation and survival. Ectonucleotidase CD39 has anti-inflammatory properties as it hydrolyzes pro-inflammatory extra-cellular ATP, generates anti-inflammatory adenosine and also protects regulatory T cells from ATP-induced cell death. In this study we investigated the clinical significance of CD39 expression on CD4+T-cells in 45 patients with CLL as well as its compartmental regulation and explored the possible mechanisms for its induction. Compared to healthy individuals, CD4+CD39+ lymphocytes were increased in the peripheral blood of patients with CLL (4.6%±2.28 vs. 17.3%±12.49, respectively, p=0.004), and correlated with advanced stage of disease (9.72%±5.76, 18.15%±12.03 and 25.90%±16.34, of CD4+ lymphocytes, in patients with Rai stages 0, 1+2 and 3+4, respectively, p=0.019). CD4+CD39+ cells were also higher in patients with CLL who needed therapeutic intervention (untreated; 12.99%±10.63 vs treated; 22.21%±12.88, p=0.01) and in those who were ZAP70+ or had b2-microglobulin levels>3g/L. There were more CD4+CD39+ lymphocytes in the bone marrow compartment (22.25%±16.16) than in the peripheral blood (16.60%±15.84, p=0.009). In-vitro studies showed that CD39 can be induced on CD4+cells by exposure to ATP or indirectly, following B-cell receptor (BCR) engagement (CD4+CD39+ lymphocytes increased by 1.56 fold, in the BCR engaged samples compared to their paired controls; 20.27%±11.3 vs. 13%±9.42, respectively, p=0.0006). Conclusions: Increased CD39 expression on CD4+ T-lymphocytes in CLL associates with an aggressive disease. This may reflect the ability of the leukemic cells to suppress the surrounding immune environment, and contribute to a poorer prognosis. CD39+ may also serve as a future target for the development of novel therapies with immune modulating anti–tumor agents in CLL. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2004 ◽  
Vol 103 (5) ◽  
pp. 1968-1969 ◽  
Author(s):  
Ozren Jaksic ◽  
Mirjana Mariana Kardum Paro ◽  
Ika Kardum Skelin ◽  
Rajko Kusec ◽  
Vlatko Pejsa ◽  
...  

2021 ◽  
Author(s):  
Man Chen ◽  
Huipeng Sun ◽  
Lina Zhang ◽  
Haiyan Gao ◽  
Minjing Fu ◽  
...  

Abstract Background: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is the most prevalent adult leukemia, and its incidence continues to rise year after year. Rapid and precise diagnosis is an essential element in effective case management, however, the clinical diagnosis, treatment, and prognosis of CLL/SLL are not fully elucidated. Case presentation: we report the case of a 66-year-old man with atypical CLL/SLL. The white blood cell (WBC) count (842.0 × 109/L), platelet count (30.6 × 109/L), and abnormal lymphocytes were increased in peripheral blood. Flow cytometry showed 98.34% of nucleated cells were malignant monoclonal mature B cell. Peripheral blood smear found the leukocytes and lymphocytes with abnormal morphology were increased. Fluorescence in situ hybridization showed CCND1 (11q23)/IGH (14q32) and abnormal chromosome 12 were invisible, 91%-93% of interphase nuclei presented D13S319 and TP53, 17p13.1 loss. Histopathology analysis of bone marrow observed the proliferation centers with immunoblasts. Immunohistochemistry showed that bone marrow was positive for PAX-5, CD20, CD23, and CD5, negative for CD3, cyclinD1, and sox11, and partial positive for Ki67. The patient was diagnosed as CLL/SLL based on above clinical and laboratory findings. The patient was managed with oral 50 mg Vinetoc, fluid replacement, hydration and alkalinization, and the symptoms were significantly relieved. Conclusions: This report further expands the knowledge of clinical diagnosis and treatment of atypical CLL/SLL.


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