Background: Accelerated-chronic lymphocytic leukemia (A-CLL) is a rare disease entity as it represents less than 1% of all reported cases of chronic lymphoid leukemia (CLL). Moreover, it is most likely an under diagno...Background: Accelerated-chronic lymphocytic leukemia (A-CLL) is a rare disease entity as it represents less than 1% of all reported cases of chronic lymphoid leukemia (CLL). Moreover, it is most likely an under diagnosed entity due to its rarity and the non-standardized practice of lymph node biopsy in CLL. Purpose: The aims of our work are to establish the diagnosis of A-CLL and to study the prognosis and treatment of this rare entity. Method: here, we report the clinical presentation and the follow up of two cases of A-CLL. Results: Distinguishing Richter transformation (RT) from A-CLL is important as it may result in a major change in disease management. The prognosis of A-CLL is intermediate between CLL and RT. The prognosis is mainly poor due to a predominance of poor prognostic markers including an increasing number of p53-positive cases. Conclusion: To this date, no prospective study has been led to define the best treatment for A-CLL. The shorter survival of A-CLL when compared to typical CLL implies the need of a more aggressive treatment.展开更多
Chronic lymphocytic leukemia(CLL) is the most common leukemia in the western world. Despite significantadvances in therapy over the last decade CLL remains incurable. Current front-line therapy often consists of chemo...Chronic lymphocytic leukemia(CLL) is the most common leukemia in the western world. Despite significantadvances in therapy over the last decade CLL remains incurable. Current front-line therapy often consists of chemoimmunotherapy-based regimens, most commonly the fludarabine, cyclophosphamide plus rituximab combination, but rates of relapse and refractory disease are high among these patients. Several key signaling pathways are now known to mediate the survival and proliferation of CLL cells in vivo, the most notable of which are the pathways mediated by the B-cell receptor(BCR) and cytokine receptors. A better understanding of the pathogenesis of the disease, the underlying biology of the CLL-cell and the roles of the tumour microenvironment has provided the rationale for trials of a range of novel, more targeted therapeutic agents. In particular, clinical trials of ibrutinib and idelalisib, which target the Brutons tyrosine kinase and the delta isoform of phosphoinositol-3 kinase components of the BCR signaling pathway respectively, have shown extremely promising results. Here we review the current literature on the key signaling pathways and interactions of CLL cells that mediate the survival and proliferation of the leukemic cells. For each we describe the results of the recent clinical trials and in vitro studies of novel therapeutic agents.展开更多
Chemoimmunotherapy(CIT)is defined as standard first line treatment for chronic lymphocytic leukemia(CLL)patients while patients with unfavorable biological characteristics such as unmutated immunoglobulin heavy chain(...Chemoimmunotherapy(CIT)is defined as standard first line treatment for chronic lymphocytic leukemia(CLL)patients while patients with unfavorable biological characteristics such as unmutated immunoglobulin heavy chain(UM-IGHV)and TP53 aberration failed to benefit from it.The emergency of the small molecular targeted agents including Bruton’s tyrosine kinase(BTK)inhibitor(BTKi)leads to a brand-new era,from a CIT to a chemo-free era in CLL.However,the treatment of target agents is not enough to attain a deep remission and high rate of complete remission(CR),especially in patients with high risks.The long duration brought about problems,such as cost,drug resistance and toxicity.To benefit CLL in progression free survival(PFS)and long-term remission,exploration of time-limited therapies,mainly with BTKi plus CIT and BCL2i based combination therapy has become a mainstream in clinical trials.The time-limited combination therapy shed light on the promising potentiality to attain sustainable deep remission and partly overcame the risk factors,although long term follow-up is required to consolidate the conclusion.In this review,we intend to introduce key results of clinical trials with combination therapy,discuss the achievements and limitations and put forward future direction for clinical trial design in this field.展开更多
BACKGROUND The concurrence of acute myeloid leukemia(AML)and chronic lymphocytic leukemia(CLL)is rare.Previous reports of such cases have focused mainly on clinical diagnosis and characteristics,so the mechanism remai...BACKGROUND The concurrence of acute myeloid leukemia(AML)and chronic lymphocytic leukemia(CLL)is rare.Previous reports of such cases have focused mainly on clinical diagnosis and characteristics,so the mechanism remains unclear,and therapy options have been poorly explored.CASE SUMMARY Here,we report two cases of synchronous AML and CLL.Flow cytometry revealed two distinct abnormal cell populations(myeloblasts and lymphoid cells)according to scatter characteristics.CD5-positive B cell lymphoma with myeloid leukemia invasion was observed on lymph node biopsy.Chemotherapy regimens indicated for both AML and CLL were used in our patients,and our patients achieved complete response after chemotherapy.Next-generation sequencing of 88 genes was performed.CONCLUSION We conclude that early mutation and dysregulation at the hematopoietic stem cell stage and the accumulation of multiple rearrangements may cause the concurrence of CLL and AML.The treatment of infection and combination therapy aimed at the CLL component are significant in the management of patients with concurrent CLL and AML.展开更多
Determination of minimal residual disease (MRD) remains crucial for the follow-up after therapy in chronic lymphocytic leukemia (CLL) patients. Chimerism was assessed by short tandem repeat (STR)-PCR and single nucleo...Determination of minimal residual disease (MRD) remains crucial for the follow-up after therapy in chronic lymphocytic leukemia (CLL) patients. Chimerism was assessed by short tandem repeat (STR)-PCR and single nucleotide polymorphisms (SNP)-PCR, and MRD by a multicolor flow cytometric approach in 12 consecutive patients with CLL after they received allogeneic stem cell transplantation (SCT). Overall, 11 patients achieved MRD flow negativity [10 had full donor chimerism (FDC) and one had mixed chimerism (MC)]. Only one patient remained with MRD flow positivity and displayed MC. Fifty-six samples were concomitantly studied by both chimerism and MRD flow. A significant correlation was observed between MRD flow data and chimerism in both PB and BM by using a mixed effect linear regression (p < 0.001). Flow cytometry approach of MRD can be easily combined with chimerism during the follow-up post-allogeneic SCT. Both techniques appeared complementary for guiding post-transplant immunomodulation.展开更多
Papular mycosis fungoides(MF) is a rare presentation of MF. Six illustrative cases of papular MF were retrospectively reviewed. Five of the cases studied by immunohistochemistry had variable numbers(range: 1%-20%) of ...Papular mycosis fungoides(MF) is a rare presentation of MF. Six illustrative cases of papular MF were retrospectively reviewed. Five of the cases studied by immunohistochemistry had variable numbers(range: 1%-20%) of CD30+ cells in the dermal infiltrate, a finding that is characteristic of lymphomatoid papulosis but may occasionally occur in typical early MF. Although none of our papular MF patients had progressive disease, lesions with relatively high numbers of CD30+ cells in 3 patients did not respond well to skin-directed treatments used for MF. Interestingly, these patients had evidence of coexisting clonal B cell populations in the blood(one with clonal B cell lymphocytosis and two with B-cell chronic lymphocytic leukemia). We conclude that:(1) papular MF may contain CD30+ cells, thereby causing confusion with lymphomatoid papulosis; and(2) papular MF, like more typical MF, may be associated with clonal B-cell proliferations including chronic lymphocytic leukemia.展开更多
Objective:This study aims to evaluate the natural history of patients with chronic lymphocytic leukemia(CLL)and a 17p deletion(17p-)and identify the predictive factors within this subgroup.Methods:The sample of patien...Objective:This study aims to evaluate the natural history of patients with chronic lymphocytic leukemia(CLL)and a 17p deletion(17p-)and identify the predictive factors within this subgroup.Methods:The sample of patients with CLL were analyzed by fluorescence in situ hybridization for deletions in chromosome bands 11q22,13q14 and 17p13;trisomy of bands 12q13;and translocation involving band 14q32.The data from 456 patients with or without a 17p-were retrospectively collected and analyzed.Results:The overall response rate(ORR)in patients with a 17p-was 56.9%,and patients with a high percentage of 17p-(defined as more than 25%of cells harbouring a 17p-)had a lower ORR.The median overall survival(OS)in patients with a 17p-was 78.0 months,which was significantly shorter than the OS in patients without this genetic abnormality(median 162.0 months,P<0.001).Within the subgroup with a 17p-,the progression-free survival was significantly shorter in patients at Binet stage B-C and patients with elevated lactate dehydrogenase(LDH),B symptoms,unmutated IGHV and a high percentage of 17p-.Conclusions:These results indicated that patients with a 17p-CLL have a variable prognosis that might be predicted using simple clinical and laboratory characteristics.展开更多
Curcumin is a widely researched natural product and is known to possess anticarcinogenic properties.Chronic lymphocytic leukemia is a type of leukemia that principally affects patients with age higher than 60 years.Si...Curcumin is a widely researched natural product and is known to possess anticarcinogenic properties.Chronic lymphocytic leukemia is a type of leukemia that principally affects patients with age higher than 60 years.Since the toxicity of conventional drugs exceeds the benefits of treating this leukemia type,patients are treated only in the advanced symptomatic stages.The current article reviews curcumin,its general actions and targets in cancer,and specifically that of it in chronic lymphocytic leukemia.展开更多
Background: High levels of MCL-1 and BCL-2 proteins have been found in Chronic Lymphocytic Leukemia (CLL), and inversely correlated with response to treatment. BCL-2/Bax ratio is the main director of apoptosis in CLL....Background: High levels of MCL-1 and BCL-2 proteins have been found in Chronic Lymphocytic Leukemia (CLL), and inversely correlated with response to treatment. BCL-2/Bax ratio is the main director of apoptosis in CLL. The study aimed to clarify the prognostic role of MCL-1, BCL-2 and BCL-2/ Bax ratio in B-CLL. Patients & method: Estimation of MCL-1, BCL-2 and Bax expressions by a flow cytometry in 45 B-CLL patients and the prognostic value of these markers were correlated with other well-known established prognostic markers and treatment response. Results: MCL-1 was expressed in 60% of cases while BCL-2 was expressed in 82.2% of cases. MCL-1 expression was significantly high in male gender, short lymphocyte doubling time (LDT), and high expression of CD 38 (p β2M, CD38 expression), low ZAP-70 expression, splenomegaly and higher Rai stage were significantly increased in patients with high expression of BCL-2 (p β2M, high C-D38 expression, low ZAP-70 expression, the poor cytogenetic and splenomegaly in patients with high expression of BCL-2/ Bax ratio (p In conclusion: MCL-1, BCL-2 expressions and BCL-2/Bax ratio could be useful potential predictive and prognostic markers in B-CLL.展开更多
Introduction: Chronic lymphocytic leukemia (CLL) is a disease of the elderly. Elderly patients often have increased comorbidity burden and loss of organ reserve that may impact their ability to tolerate cancer therapy...Introduction: Chronic lymphocytic leukemia (CLL) is a disease of the elderly. Elderly patients often have increased comorbidity burden and loss of organ reserve that may impact their ability to tolerate cancer therapy. We described realworld characteristics of typical CLL patients and identified factors predictive of receiving treatment. Methods: A retrospective cohort analysis of 8343 first primary CLL patients was performed using the linked Surveillance, Epidemiology, and End Results-Medicare database. Patients were diagnosed from 1/1/1998 to 12/31/2007, >66 years, and continuously enrolled in Medicare Parts A and B in the year prior to diagnosis. Comorbidity was examined using the National Cancer Institute comorbidity index and the Cumulative Illness Rating Scale. Cox and Logistic regression modeling assessed patient characteristics predictive of receiving treatment within the first year after diagnosis. Results: Median follow-up time from diagnosis was 782 days. During the study time period, there were 3366 (40%) treated patients and 4977 (60%) untreated. Even among those diagnosed with advanced stage (n = 4213), 57% were not treated. Treated patients were younger at diagnosis compared to untreated (76 vs. 79;p < 0.0001). In general, as age increased, the incidence and severity of comorbidities increased. In multivariate regression analyses, the treatment rate was significantly lower among patients >80 years, females, and with early stage disease;and significantly decreased with increasing comorbidity burden. Conclusions: Age, gender, comorbidity and stage were predictive of receiving treatment. Among patients with advanced stage, 57% were not being treated possibly due to older age and/or higher comorbidity burden.展开更多
Objective: No studies of either the cross-sectional or prospective association of behavioral lifestyle characteristics and the onset of Chronic Lymphocytic Leukemia (CLL) exist. Methods: Multiple interview or question...Objective: No studies of either the cross-sectional or prospective association of behavioral lifestyle characteristics and the onset of Chronic Lymphocytic Leukemia (CLL) exist. Methods: Multiple interview or questionnaire measures of emotional distress and social support, as well as personality characteristics, exercise, sleep quality, aspirin or lipid-lowering medication use, smoking status and history, educational history and farming/pesticide exposure were tested as correlates of age at initial diagnosis of CLL (AAID-CLL) in 183 patients recruited from the electronic records of Henry Ford Hospital or internet support sites. Results: Aspirin use, having always been “Fit” and living alone were positively associated with AAID. Negative associations were observed for farming/pesticide exposure, years of education, being married, self description as a “Lone Wolf” or “Worrier”, taking “nerve” or “sleeping” pills, awakenings per night, Packyears of Smoking and the Interpersonal Sensitivity, Depression, Anxiety, Hostility and Paranoia scales of the Symptom Checklist 90 - Revised, as well as the AIAI (anger), Depression and Anxiety scales of the Spouse/Friend Ketterer Stress Symptom Frequency Checklist. Conclusions: Aspirin use and exercise may exert a modifiable delaying influence in the onset of CLL. Conversely, emotional distress and smoking may hasten its onset. Prospective, and interventional, tests of these findings are needed.展开更多
BACKGROUND Langerhans cell sarcoma(LCS)is a rare malignancy with poor prognosis.LCS and chronic lymphocytic leukemia(CLL)/small lymphocytic lymphoma(SLL)can occur in the same diseased tissues,such as lymph nodes or sk...BACKGROUND Langerhans cell sarcoma(LCS)is a rare malignancy with poor prognosis.LCS and chronic lymphocytic leukemia(CLL)/small lymphocytic lymphoma(SLL)can occur in the same diseased tissues,such as lymph nodes or skin.CASE SUMMARY A 48-year-old female Han Chinese patient was admitted for generalized lymph node enlargement for 6 years and abdominal distension for 1 wk.She was diagnosed with small B-cell lymphoma(stage IV)/CLL(Benet stage B)and received chemotherapy.She started oral ibrutinib in February 2019.She was hospitalized on June 11,2019,and a 1.5 cm×1.5 cm dark-red nodule with ulceration scalp lesion was found.Biopsy revealed LCS but without CLL/SLL.She was diagnosed with CLL/SLL(Binet stage C,Rai stage IV)accompanied by secondary histiocytic sarcomas and skin LCS and received cyclophosphamide,doxorubicin,vincristine,dexamethasone,and etoposide but developed severe cytopenia.She ultimately refused treatments and discharged spontaneously.She died on September 12,2019.The literature review showed that in patients with CLL/SLL,skin lesions of LCS are accompanied by CLL/SLL.This patient was different from the previously reported cases of skin LCS in patients with CLL/SLL.CONCLUSION In this patient,the skin lesion of LCS showed no concomitant CLL/SLL.展开更多
Purpose: To determine the effect of curcumin (as Meriva) on absolute lymphocyte count (ALC), T cell populations and NK cells in patients with Rai stage 0/1 chronic lymphocytic leukemia (CLL) over a period of six month...Purpose: To determine the effect of curcumin (as Meriva) on absolute lymphocyte count (ALC), T cell populations and NK cells in patients with Rai stage 0/1 chronic lymphocytic leukemia (CLL) over a period of six months. Experimental Design: Twenty-one patients with significant lymphocytosis (>20 × 109 lymphocytes/L) and stage 0/1 CLL were recruited into the study and received oral curcumin 2 grams/day. Blood samples were collected at baseline and at 2 monthly intervals for six months for full blood count, leukocyte surface antigens, liver function, serum biochemistry, immunoglobulins, CRP and ESR. A positive biologic response was defined as a reduction in the ALC of more than 20% from pre-treatment levels. Results: Four patients (20%) demonstrated more than 20% decrease in ALC, three of whom had lower ALC at the end of the study as compared to baseline. The decrease in ALC was accompanied by an increase in CD4, CD8 and NK cells. No demonstrable response was seen in seventeen patients (80%) who exhibited stable, fluctuating or increasing ALC during the study. Conclusion: A subgroup of stage 0/1 CLL patients may be responsive to curcumin therapy. The beneficial response appears to be immunomodulated.展开更多
Background: Bendamustine-based regimens are often used in the management of patients with chronic lymphocytic leukemia (CLL) but few studies have analyzed the comorbidity- and/or adverse event (CAE)-related healthcare...Background: Bendamustine-based regimens are often used in the management of patients with chronic lymphocytic leukemia (CLL) but few studies have analyzed the comorbidity- and/or adverse event (CAE)-related healthcare costs in patients receiving these regimens in a real-world setting. Aims: To describe all-cause and CAE-related healthcare costs in relapse/refractory (R/R) elderly patients with CLL treated with bendamustine-based regimens in a real-world setting. Methods: Adult patients with R/R CLL who received bendamustine-based regimens on/after January 2010 were selected from the Medicare Limited Data Set (LDS) 5% Standard Analytic Files. Selected patients were classified into cohorts based on the two most prevalent bendamustine-based regimens observed (index treatment): 1) bendamustine + rituximab (BR cohort) and 2) bendamustine monotherapy (B-mono cohort). For each cohort, all-cause and CAE-related healthcare costs, while on treatment, were reported per-patient-per-month (PPPM). Overall survival (OS) rates following initiation of the index treatment were described using age- and gender-adjusted Kaplan-Meier curves. Results: A total of 275 patients were included in the BR cohort and 100 patients in the B-mono cohort. Most patients were male and the mean age was approximately 75 years old. During treatment, total all-cause healthcare costs were $14,520 PPPM for the BR cohort and $13,125 PPPM for the B-mono cohort—outpatient costs (mainly driven by CLL-drug costs) represented 86.1% of the total all-cause healthcare costs for the BR cohort and 69.8% for the B-mono cohort. CAE costs accounted for 58.3% of the total all-cause healthcare costs for the BR cohort and 66.9% for the B-mono cohort. Median OS was 35 months in the BR cohort and 21 months in the B-mono cohort. Conclusion: In this population of elderly patients with R/R CLL treated with bendamustine-based regimens, CAEs were common and translated into important medical costs. Median OS was also relatively short suggesting an unmet medical need.展开更多
CD40 ligation provides signals central to chronic lymphocytic leukemia (CLL) cell survival and proliferation. The release of soluble CD40 (sCD40) may impact on both these signals and CD40 targeted therapies. In this s...CD40 ligation provides signals central to chronic lymphocytic leukemia (CLL) cell survival and proliferation. The release of soluble CD40 (sCD40) may impact on both these signals and CD40 targeted therapies. In this study we investigated the prognostic significance of plasma sCD40 inuntreated CLL patients (n = 34). We report that 56% had levels higher than those of normal donors and that elevated levels were associated with significantly shorter treatment free (TFS) and overall survival. In bivariate analysis sCD40 remained a significant marker of TFS independent of Binet staging, CD38 positivity and lymphocyte count. RT-PCR analysis demonstrated that CLL cells expressed transcripts encoding putative sCD40. These results suggest sCD40 may play a role in CLL progression and that its function, prognostic significance and potential impact on antibody based therapies should be further investigated.展开更多
Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course. Microarray studies allowed highlight genes differentially expressed in this pathology. In this study, we have evaluated the pro...Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course. Microarray studies allowed highlight genes differentially expressed in this pathology. In this study, we have evaluated the prognostic significance of SEPT10 expression in CLL patients. Results were correlated with immunoglobulin heavy-chain variable (IGHV) genes mutational status, genomic rearrangements and clinical parameters. SEPT10 mRNA levels were determined by quantitative real-time PCR in 70 newly diagnosed CLL patients consecutively referred to our Institution. A wide heterogeneity for SEPT10 expression was found. Gene upregulation was observed in 18.5% of cases. The univariate analysis showed a positive association between gen expression and platelet count (p 0.0001) and a negative correlation with hemoglobin levels (p = 0.0094). Although no significant differences were observed, mean treatment free survival was shorter in patients with high expression (31 months) with respect to those with low mRNA levels (72 months). Cases with abnormal karyotypes had increased expression compared to those with normal karyotypes and no association between gene expression and FISH (fluorescence in situ hybridization) risk groups and IGHV mutational status was found. Cases using IGHV3-23 gene rearrangement had low SEPT10 expression. Our results showed an association between SEPT10 expression and features of adverse outcome but without independent prognostic value. The study of SEPT10 expression may be important for a better understanding of disease heterogeneity, adding further information to those provided by established prognostic factors.展开更多
Background: Central neurological involvement is the most frequent extra hematological manifestation of chronic lymphocytic leukemia;it is multifactorial and rarely due to a cerebral localization of the disease. We rep...Background: Central neurological involvement is the most frequent extra hematological manifestation of chronic lymphocytic leukemia;it is multifactorial and rarely due to a cerebral localization of the disease. We report a case of cerebral localization of chronic lymphoid leukemia whose clinical and radiological aspects were very suggestive of progressive multifocal leukoencephalopathy. Case Presentation: A 65-year-old patient who was HIV-negative (human immunodeficiency virus), had consulted for bilateral axillary, cervical and inguinal lymphadenopathy associated with major asthenia and hyper lymphocytosis (lymphocyte count was 11 giga/l). Chronic lymphocyticleukemia with TP53 mutation was diagnosed and treatment with Ibrutinib 420 mg/day was initiated. After 2 months of treatment, the evolution was marked by the onset of neurological disorders whose clinical-radiological presentation and temporal evolution had led to the diagnosis of progressive multifocal leukoencephalopathy. In the absence of virological evidence in the cerebrospinal fluid analysis, a stereotactic biopsy of the brain lesions had been performed, making it possible to formally rule out this infectious hypothesis and to demonstrate cerebral invasion by tumour cells. Immuno-chemotherapy combining Rituximab-Cyclophosphamide-Doxorubicin-Vincristine-Prednisone-Ibrutinib (RCHOP-Ibrutinib) with intrathecal chemotherapy resulted in a very good clinical-radiological response. Conclusion: The appearance of neurological manifestations in the context of chronic lymphocytic leukemia must systematically lead to a search for a cerebral localization of the disease. In the absence of virological evidence in the cerebrospinal fluid, any suspicion of progressive multifocal leukoencephalopathy in this context should lead to the histological study of brain lesions.展开更多
Objective: To report a case of Chronic Lymphoid Leukemia in a 28-year-old young subject, with variable clinical features and a TP53 mutation, diagnosed and followed up in the Onco-Hematology department of the HNN. Obs...Objective: To report a case of Chronic Lymphoid Leukemia in a 28-year-old young subject, with variable clinical features and a TP53 mutation, diagnosed and followed up in the Onco-Hematology department of the HNN. Observation: 28-year-old patient, having consulted for polyadenopathy and physical asthenia, whose clinical examination found a conscious patient, submaxillary, laterocervical, axillary and inguinal lymphadenopathy, bilateral, symmetrical, painless and non-compressive whose largest measures 3 cm in diameter. Hepato-splenomegaly and epistaxis. Predominantly lymphocyte hyperleukocytosis, immunophenotyping revealed low CD19+, CD5+, CD23+, CD20 monoclonal B lymphoid proliferation. The Matutes score was 4. A karyotype showed a three-chromosome translocation;the short arm of a chromosome 2, the long arm of a chromosome 11 and the long arm of a chromosome 13, and a translocation between the long arm of a chromosome 6 and the long arm of a chromosome 18. A FISH objectified a led 17p. The diagnosis of Binet Stage C CLL with positive del 17p and complex karyotype was retained. Despite the poor prognosis, the R-C (Rituximab-Chlorambucil) protocol was instituted with once-weekly transfusions. The patient is still alive in partial clinical and biological remission. Conclusion: Despite therapeutic progress, the presence of the deletion of chromosome 17p with TP53 mutation and the young age of the patient does not change the patient’s prognosis.展开更多
文摘Background: Accelerated-chronic lymphocytic leukemia (A-CLL) is a rare disease entity as it represents less than 1% of all reported cases of chronic lymphoid leukemia (CLL). Moreover, it is most likely an under diagnosed entity due to its rarity and the non-standardized practice of lymph node biopsy in CLL. Purpose: The aims of our work are to establish the diagnosis of A-CLL and to study the prognosis and treatment of this rare entity. Method: here, we report the clinical presentation and the follow up of two cases of A-CLL. Results: Distinguishing Richter transformation (RT) from A-CLL is important as it may result in a major change in disease management. The prognosis of A-CLL is intermediate between CLL and RT. The prognosis is mainly poor due to a predominance of poor prognostic markers including an increasing number of p53-positive cases. Conclusion: To this date, no prospective study has been led to define the best treatment for A-CLL. The shorter survival of A-CLL when compared to typical CLL implies the need of a more aggressive treatment.
文摘Chronic lymphocytic leukemia(CLL) is the most common leukemia in the western world. Despite significantadvances in therapy over the last decade CLL remains incurable. Current front-line therapy often consists of chemoimmunotherapy-based regimens, most commonly the fludarabine, cyclophosphamide plus rituximab combination, but rates of relapse and refractory disease are high among these patients. Several key signaling pathways are now known to mediate the survival and proliferation of CLL cells in vivo, the most notable of which are the pathways mediated by the B-cell receptor(BCR) and cytokine receptors. A better understanding of the pathogenesis of the disease, the underlying biology of the CLL-cell and the roles of the tumour microenvironment has provided the rationale for trials of a range of novel, more targeted therapeutic agents. In particular, clinical trials of ibrutinib and idelalisib, which target the Brutons tyrosine kinase and the delta isoform of phosphoinositol-3 kinase components of the BCR signaling pathway respectively, have shown extremely promising results. Here we review the current literature on the key signaling pathways and interactions of CLL cells that mediate the survival and proliferation of the leukemic cells. For each we describe the results of the recent clinical trials and in vitro studies of novel therapeutic agents.
基金grants from the National Natural Science Foundation of China(No.81970146)National Science Foundation of China International Cooperation and Exchange Program(No.81720108002)+1 种基金National Science and Technology Major Project(No.2018ZX09734007)Six Talent Peaks Project in Jiangsu Province,2019(No.WSN-001).
文摘Chemoimmunotherapy(CIT)is defined as standard first line treatment for chronic lymphocytic leukemia(CLL)patients while patients with unfavorable biological characteristics such as unmutated immunoglobulin heavy chain(UM-IGHV)and TP53 aberration failed to benefit from it.The emergency of the small molecular targeted agents including Bruton’s tyrosine kinase(BTK)inhibitor(BTKi)leads to a brand-new era,from a CIT to a chemo-free era in CLL.However,the treatment of target agents is not enough to attain a deep remission and high rate of complete remission(CR),especially in patients with high risks.The long duration brought about problems,such as cost,drug resistance and toxicity.To benefit CLL in progression free survival(PFS)and long-term remission,exploration of time-limited therapies,mainly with BTKi plus CIT and BCL2i based combination therapy has become a mainstream in clinical trials.The time-limited combination therapy shed light on the promising potentiality to attain sustainable deep remission and partly overcame the risk factors,although long term follow-up is required to consolidate the conclusion.In this review,we intend to introduce key results of clinical trials with combination therapy,discuss the achievements and limitations and put forward future direction for clinical trial design in this field.
文摘BACKGROUND The concurrence of acute myeloid leukemia(AML)and chronic lymphocytic leukemia(CLL)is rare.Previous reports of such cases have focused mainly on clinical diagnosis and characteristics,so the mechanism remains unclear,and therapy options have been poorly explored.CASE SUMMARY Here,we report two cases of synchronous AML and CLL.Flow cytometry revealed two distinct abnormal cell populations(myeloblasts and lymphoid cells)according to scatter characteristics.CD5-positive B cell lymphoma with myeloid leukemia invasion was observed on lymph node biopsy.Chemotherapy regimens indicated for both AML and CLL were used in our patients,and our patients achieved complete response after chemotherapy.Next-generation sequencing of 88 genes was performed.CONCLUSION We conclude that early mutation and dysregulation at the hematopoietic stem cell stage and the accumulation of multiple rearrangements may cause the concurrence of CLL and AML.The treatment of infection and combination therapy aimed at the CLL component are significant in the management of patients with concurrent CLL and AML.
文摘Determination of minimal residual disease (MRD) remains crucial for the follow-up after therapy in chronic lymphocytic leukemia (CLL) patients. Chimerism was assessed by short tandem repeat (STR)-PCR and single nucleotide polymorphisms (SNP)-PCR, and MRD by a multicolor flow cytometric approach in 12 consecutive patients with CLL after they received allogeneic stem cell transplantation (SCT). Overall, 11 patients achieved MRD flow negativity [10 had full donor chimerism (FDC) and one had mixed chimerism (MC)]. Only one patient remained with MRD flow positivity and displayed MC. Fifty-six samples were concomitantly studied by both chimerism and MRD flow. A significant correlation was observed between MRD flow data and chimerism in both PB and BM by using a mixed effect linear regression (p < 0.001). Flow cytometry approach of MRD can be easily combined with chimerism during the follow-up post-allogeneic SCT. Both techniques appeared complementary for guiding post-transplant immunomodulation.
文摘Papular mycosis fungoides(MF) is a rare presentation of MF. Six illustrative cases of papular MF were retrospectively reviewed. Five of the cases studied by immunohistochemistry had variable numbers(range: 1%-20%) of CD30+ cells in the dermal infiltrate, a finding that is characteristic of lymphomatoid papulosis but may occasionally occur in typical early MF. Although none of our papular MF patients had progressive disease, lesions with relatively high numbers of CD30+ cells in 3 patients did not respond well to skin-directed treatments used for MF. Interestingly, these patients had evidence of coexisting clonal B cell populations in the blood(one with clonal B cell lymphocytosis and two with B-cell chronic lymphocytic leukemia). We conclude that:(1) papular MF may contain CD30+ cells, thereby causing confusion with lymphomatoid papulosis; and(2) papular MF, like more typical MF, may be associated with clonal B-cell proliferations including chronic lymphocytic leukemia.
基金supported by grants from the National Nature Science Foundation of China (No. 81200395, 81370632)the National Science and Technology supporting Program (No. 2014BAI09B12)+1 种基金the Fundamental Application and Advanced Technology Research Program of Tianjin (No. 15JCYBJC27900)the National Public Health Grand Research Foundation (No. 201202017)
文摘Objective:This study aims to evaluate the natural history of patients with chronic lymphocytic leukemia(CLL)and a 17p deletion(17p-)and identify the predictive factors within this subgroup.Methods:The sample of patients with CLL were analyzed by fluorescence in situ hybridization for deletions in chromosome bands 11q22,13q14 and 17p13;trisomy of bands 12q13;and translocation involving band 14q32.The data from 456 patients with or without a 17p-were retrospectively collected and analyzed.Results:The overall response rate(ORR)in patients with a 17p-was 56.9%,and patients with a high percentage of 17p-(defined as more than 25%of cells harbouring a 17p-)had a lower ORR.The median overall survival(OS)in patients with a 17p-was 78.0 months,which was significantly shorter than the OS in patients without this genetic abnormality(median 162.0 months,P<0.001).Within the subgroup with a 17p-,the progression-free survival was significantly shorter in patients at Binet stage B-C and patients with elevated lactate dehydrogenase(LDH),B symptoms,unmutated IGHV and a high percentage of 17p-.Conclusions:These results indicated that patients with a 17p-CLL have a variable prognosis that might be predicted using simple clinical and laboratory characteristics.
文摘Curcumin is a widely researched natural product and is known to possess anticarcinogenic properties.Chronic lymphocytic leukemia is a type of leukemia that principally affects patients with age higher than 60 years.Since the toxicity of conventional drugs exceeds the benefits of treating this leukemia type,patients are treated only in the advanced symptomatic stages.The current article reviews curcumin,its general actions and targets in cancer,and specifically that of it in chronic lymphocytic leukemia.
文摘Background: High levels of MCL-1 and BCL-2 proteins have been found in Chronic Lymphocytic Leukemia (CLL), and inversely correlated with response to treatment. BCL-2/Bax ratio is the main director of apoptosis in CLL. The study aimed to clarify the prognostic role of MCL-1, BCL-2 and BCL-2/ Bax ratio in B-CLL. Patients & method: Estimation of MCL-1, BCL-2 and Bax expressions by a flow cytometry in 45 B-CLL patients and the prognostic value of these markers were correlated with other well-known established prognostic markers and treatment response. Results: MCL-1 was expressed in 60% of cases while BCL-2 was expressed in 82.2% of cases. MCL-1 expression was significantly high in male gender, short lymphocyte doubling time (LDT), and high expression of CD 38 (p β2M, CD38 expression), low ZAP-70 expression, splenomegaly and higher Rai stage were significantly increased in patients with high expression of BCL-2 (p β2M, high C-D38 expression, low ZAP-70 expression, the poor cytogenetic and splenomegaly in patients with high expression of BCL-2/ Bax ratio (p In conclusion: MCL-1, BCL-2 expressions and BCL-2/Bax ratio could be useful potential predictive and prognostic markers in B-CLL.
文摘Introduction: Chronic lymphocytic leukemia (CLL) is a disease of the elderly. Elderly patients often have increased comorbidity burden and loss of organ reserve that may impact their ability to tolerate cancer therapy. We described realworld characteristics of typical CLL patients and identified factors predictive of receiving treatment. Methods: A retrospective cohort analysis of 8343 first primary CLL patients was performed using the linked Surveillance, Epidemiology, and End Results-Medicare database. Patients were diagnosed from 1/1/1998 to 12/31/2007, >66 years, and continuously enrolled in Medicare Parts A and B in the year prior to diagnosis. Comorbidity was examined using the National Cancer Institute comorbidity index and the Cumulative Illness Rating Scale. Cox and Logistic regression modeling assessed patient characteristics predictive of receiving treatment within the first year after diagnosis. Results: Median follow-up time from diagnosis was 782 days. During the study time period, there were 3366 (40%) treated patients and 4977 (60%) untreated. Even among those diagnosed with advanced stage (n = 4213), 57% were not treated. Treated patients were younger at diagnosis compared to untreated (76 vs. 79;p < 0.0001). In general, as age increased, the incidence and severity of comorbidities increased. In multivariate regression analyses, the treatment rate was significantly lower among patients >80 years, females, and with early stage disease;and significantly decreased with increasing comorbidity burden. Conclusions: Age, gender, comorbidity and stage were predictive of receiving treatment. Among patients with advanced stage, 57% were not being treated possibly due to older age and/or higher comorbidity burden.
文摘Objective: No studies of either the cross-sectional or prospective association of behavioral lifestyle characteristics and the onset of Chronic Lymphocytic Leukemia (CLL) exist. Methods: Multiple interview or questionnaire measures of emotional distress and social support, as well as personality characteristics, exercise, sleep quality, aspirin or lipid-lowering medication use, smoking status and history, educational history and farming/pesticide exposure were tested as correlates of age at initial diagnosis of CLL (AAID-CLL) in 183 patients recruited from the electronic records of Henry Ford Hospital or internet support sites. Results: Aspirin use, having always been “Fit” and living alone were positively associated with AAID. Negative associations were observed for farming/pesticide exposure, years of education, being married, self description as a “Lone Wolf” or “Worrier”, taking “nerve” or “sleeping” pills, awakenings per night, Packyears of Smoking and the Interpersonal Sensitivity, Depression, Anxiety, Hostility and Paranoia scales of the Symptom Checklist 90 - Revised, as well as the AIAI (anger), Depression and Anxiety scales of the Spouse/Friend Ketterer Stress Symptom Frequency Checklist. Conclusions: Aspirin use and exercise may exert a modifiable delaying influence in the onset of CLL. Conversely, emotional distress and smoking may hasten its onset. Prospective, and interventional, tests of these findings are needed.
文摘BACKGROUND Langerhans cell sarcoma(LCS)is a rare malignancy with poor prognosis.LCS and chronic lymphocytic leukemia(CLL)/small lymphocytic lymphoma(SLL)can occur in the same diseased tissues,such as lymph nodes or skin.CASE SUMMARY A 48-year-old female Han Chinese patient was admitted for generalized lymph node enlargement for 6 years and abdominal distension for 1 wk.She was diagnosed with small B-cell lymphoma(stage IV)/CLL(Benet stage B)and received chemotherapy.She started oral ibrutinib in February 2019.She was hospitalized on June 11,2019,and a 1.5 cm×1.5 cm dark-red nodule with ulceration scalp lesion was found.Biopsy revealed LCS but without CLL/SLL.She was diagnosed with CLL/SLL(Binet stage C,Rai stage IV)accompanied by secondary histiocytic sarcomas and skin LCS and received cyclophosphamide,doxorubicin,vincristine,dexamethasone,and etoposide but developed severe cytopenia.She ultimately refused treatments and discharged spontaneously.She died on September 12,2019.The literature review showed that in patients with CLL/SLL,skin lesions of LCS are accompanied by CLL/SLL.This patient was different from the previously reported cases of skin LCS in patients with CLL/SLL.CONCLUSION In this patient,the skin lesion of LCS showed no concomitant CLL/SLL.
文摘Purpose: To determine the effect of curcumin (as Meriva) on absolute lymphocyte count (ALC), T cell populations and NK cells in patients with Rai stage 0/1 chronic lymphocytic leukemia (CLL) over a period of six months. Experimental Design: Twenty-one patients with significant lymphocytosis (>20 × 109 lymphocytes/L) and stage 0/1 CLL were recruited into the study and received oral curcumin 2 grams/day. Blood samples were collected at baseline and at 2 monthly intervals for six months for full blood count, leukocyte surface antigens, liver function, serum biochemistry, immunoglobulins, CRP and ESR. A positive biologic response was defined as a reduction in the ALC of more than 20% from pre-treatment levels. Results: Four patients (20%) demonstrated more than 20% decrease in ALC, three of whom had lower ALC at the end of the study as compared to baseline. The decrease in ALC was accompanied by an increase in CD4, CD8 and NK cells. No demonstrable response was seen in seventeen patients (80%) who exhibited stable, fluctuating or increasing ALC during the study. Conclusion: A subgroup of stage 0/1 CLL patients may be responsive to curcumin therapy. The beneficial response appears to be immunomodulated.
文摘Background: Bendamustine-based regimens are often used in the management of patients with chronic lymphocytic leukemia (CLL) but few studies have analyzed the comorbidity- and/or adverse event (CAE)-related healthcare costs in patients receiving these regimens in a real-world setting. Aims: To describe all-cause and CAE-related healthcare costs in relapse/refractory (R/R) elderly patients with CLL treated with bendamustine-based regimens in a real-world setting. Methods: Adult patients with R/R CLL who received bendamustine-based regimens on/after January 2010 were selected from the Medicare Limited Data Set (LDS) 5% Standard Analytic Files. Selected patients were classified into cohorts based on the two most prevalent bendamustine-based regimens observed (index treatment): 1) bendamustine + rituximab (BR cohort) and 2) bendamustine monotherapy (B-mono cohort). For each cohort, all-cause and CAE-related healthcare costs, while on treatment, were reported per-patient-per-month (PPPM). Overall survival (OS) rates following initiation of the index treatment were described using age- and gender-adjusted Kaplan-Meier curves. Results: A total of 275 patients were included in the BR cohort and 100 patients in the B-mono cohort. Most patients were male and the mean age was approximately 75 years old. During treatment, total all-cause healthcare costs were $14,520 PPPM for the BR cohort and $13,125 PPPM for the B-mono cohort—outpatient costs (mainly driven by CLL-drug costs) represented 86.1% of the total all-cause healthcare costs for the BR cohort and 69.8% for the B-mono cohort. CAE costs accounted for 58.3% of the total all-cause healthcare costs for the BR cohort and 66.9% for the B-mono cohort. Median OS was 35 months in the BR cohort and 21 months in the B-mono cohort. Conclusion: In this population of elderly patients with R/R CLL treated with bendamustine-based regimens, CAEs were common and translated into important medical costs. Median OS was also relatively short suggesting an unmet medical need.
文摘CD40 ligation provides signals central to chronic lymphocytic leukemia (CLL) cell survival and proliferation. The release of soluble CD40 (sCD40) may impact on both these signals and CD40 targeted therapies. In this study we investigated the prognostic significance of plasma sCD40 inuntreated CLL patients (n = 34). We report that 56% had levels higher than those of normal donors and that elevated levels were associated with significantly shorter treatment free (TFS) and overall survival. In bivariate analysis sCD40 remained a significant marker of TFS independent of Binet staging, CD38 positivity and lymphocyte count. RT-PCR analysis demonstrated that CLL cells expressed transcripts encoding putative sCD40. These results suggest sCD40 may play a role in CLL progression and that its function, prognostic significance and potential impact on antibody based therapies should be further investigated.
文摘Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course. Microarray studies allowed highlight genes differentially expressed in this pathology. In this study, we have evaluated the prognostic significance of SEPT10 expression in CLL patients. Results were correlated with immunoglobulin heavy-chain variable (IGHV) genes mutational status, genomic rearrangements and clinical parameters. SEPT10 mRNA levels were determined by quantitative real-time PCR in 70 newly diagnosed CLL patients consecutively referred to our Institution. A wide heterogeneity for SEPT10 expression was found. Gene upregulation was observed in 18.5% of cases. The univariate analysis showed a positive association between gen expression and platelet count (p 0.0001) and a negative correlation with hemoglobin levels (p = 0.0094). Although no significant differences were observed, mean treatment free survival was shorter in patients with high expression (31 months) with respect to those with low mRNA levels (72 months). Cases with abnormal karyotypes had increased expression compared to those with normal karyotypes and no association between gene expression and FISH (fluorescence in situ hybridization) risk groups and IGHV mutational status was found. Cases using IGHV3-23 gene rearrangement had low SEPT10 expression. Our results showed an association between SEPT10 expression and features of adverse outcome but without independent prognostic value. The study of SEPT10 expression may be important for a better understanding of disease heterogeneity, adding further information to those provided by established prognostic factors.
文摘Background: Central neurological involvement is the most frequent extra hematological manifestation of chronic lymphocytic leukemia;it is multifactorial and rarely due to a cerebral localization of the disease. We report a case of cerebral localization of chronic lymphoid leukemia whose clinical and radiological aspects were very suggestive of progressive multifocal leukoencephalopathy. Case Presentation: A 65-year-old patient who was HIV-negative (human immunodeficiency virus), had consulted for bilateral axillary, cervical and inguinal lymphadenopathy associated with major asthenia and hyper lymphocytosis (lymphocyte count was 11 giga/l). Chronic lymphocyticleukemia with TP53 mutation was diagnosed and treatment with Ibrutinib 420 mg/day was initiated. After 2 months of treatment, the evolution was marked by the onset of neurological disorders whose clinical-radiological presentation and temporal evolution had led to the diagnosis of progressive multifocal leukoencephalopathy. In the absence of virological evidence in the cerebrospinal fluid analysis, a stereotactic biopsy of the brain lesions had been performed, making it possible to formally rule out this infectious hypothesis and to demonstrate cerebral invasion by tumour cells. Immuno-chemotherapy combining Rituximab-Cyclophosphamide-Doxorubicin-Vincristine-Prednisone-Ibrutinib (RCHOP-Ibrutinib) with intrathecal chemotherapy resulted in a very good clinical-radiological response. Conclusion: The appearance of neurological manifestations in the context of chronic lymphocytic leukemia must systematically lead to a search for a cerebral localization of the disease. In the absence of virological evidence in the cerebrospinal fluid, any suspicion of progressive multifocal leukoencephalopathy in this context should lead to the histological study of brain lesions.
文摘Objective: To report a case of Chronic Lymphoid Leukemia in a 28-year-old young subject, with variable clinical features and a TP53 mutation, diagnosed and followed up in the Onco-Hematology department of the HNN. Observation: 28-year-old patient, having consulted for polyadenopathy and physical asthenia, whose clinical examination found a conscious patient, submaxillary, laterocervical, axillary and inguinal lymphadenopathy, bilateral, symmetrical, painless and non-compressive whose largest measures 3 cm in diameter. Hepato-splenomegaly and epistaxis. Predominantly lymphocyte hyperleukocytosis, immunophenotyping revealed low CD19+, CD5+, CD23+, CD20 monoclonal B lymphoid proliferation. The Matutes score was 4. A karyotype showed a three-chromosome translocation;the short arm of a chromosome 2, the long arm of a chromosome 11 and the long arm of a chromosome 13, and a translocation between the long arm of a chromosome 6 and the long arm of a chromosome 18. A FISH objectified a led 17p. The diagnosis of Binet Stage C CLL with positive del 17p and complex karyotype was retained. Despite the poor prognosis, the R-C (Rituximab-Chlorambucil) protocol was instituted with once-weekly transfusions. The patient is still alive in partial clinical and biological remission. Conclusion: Despite therapeutic progress, the presence of the deletion of chromosome 17p with TP53 mutation and the young age of the patient does not change the patient’s prognosis.
