Anti-CD20 monoclonal antibodies in chronic lymphocytic leukemia

Introduction: The last decade has witnesd immense progress in the treatment of chronic lymphocytic leukemia (CLL). Chemoimmunotherapy (CIT) combining rituximab and fludarabine with cyclophosphamide (FCR) in the frontline setting has clearly been shown to improve outcomes in patients with CLL. Building on the success achieved with rituximab, other anti-CD20 monoclonal antibodies (mAbs) are being investigated. Novel bioengineering techniques have helped in the development of anti-CD20 mAbs. One antibody, ofatumumab, was recently approved for the treatment of refractory CLL. A type II anti-CD20 mAb, GA-101 (obinutuzumab), is currently in clinical trials. This short review focuses on ongoing clinical trials of anti-CD20 mAbs in CLL.

Areas covered: Literature search was performed using PubMed (www.clinicaltrials.gov (till August 2012)), and recent American Society of Clinical Oncology (ASCO), American Society of Hematology (ASH), European Hematology association (EHA), International workshop on CLL (iwCLL) abstracts, using the primary search terms ‘anti-CD20 monoclonal antibody' with/without CLL. Articles were chosen on the basis of relevance of anti-CD20 mAbs to CLL therapy.

Expert opinion: Rituximab, the prototype anti-CD20 mAb, forms the core of CIT in CLL. The success of rituximab and ofatumumab has led investigators to evaluate other anti-CD20 mAbs in the treatment of CLL.     

慢性淋巴细胞白血病免疫表型分析

目的探讨慢性淋巴细胞白血病（CLL）细胞免疫表型。方法应用流式细胞仪,选用一系列的淋巴细胞和髓系相关抗原的单抗对42例CLL患者进行淋巴细胞表面抗原检测。结果CLL患者CD5＋／CD19＋的单克隆B细胞表达占92．9％,CD5-／CD19＋的占7．1％,CD19＋／CD20＋／HLA—DR＋的占100．0％。髓系相关抗原中CD13表达率为23．8％,CD33表达率为21．4％。结论对慢性淋巴细胞白血病患者进行免疫表型分析,对于诊断和鉴别诊断有重要意义,并为临床治疗和预后评估提供依据。     

Cold agglutinin disease complicating management of aortic dissection

Background

Cold agglutinin disease is characterized by acrocyanosis, hemolytic anemia, and occasionally, frank hemoglobinuria. Although cold agglutinins are commonly detected, they are rarely clinically significant due to subphysiologic temperatures at which agglutination occurs. Cardiovascular surgical procedures requiring hypothermia present a unique challenge for these patients, requiring modification of the conduct of cardiopulmonary bypass and cardioplegia.

Complementary and alternative medicine in patients with chronic lymphocytic leukemia

Background  Despite the widespread use of complementary and alternative medicine (CAM) in the general population for the treatment of chronic diseases, only few data have been published for patients with leukemia. The aim of this survey was to study systematically the use of CAM in patients with chronic lymphocytic leukemia (CLL). Patients and methods  A structured questionnaire was sent to 247 CLL patients of all clinical stages and disease durations, treated and untreated. The questionnaire was returned anonymously by 87 patients (35%). Results  Thirty-nine patients (44%) had used alternative treatments. No correlation was seen with educational level, gender, or previous or current chemotherapy. The most common alternative or complementary treatment modality was vitamin supplementation (26%), followed by mineral (18%), homeopathic (14%), and mistletoe therapy (9.2%). Some 21% of patients considered their alternative treatment as being successful. Most patients reported that they decided to use CAM after conducting a personal investigation and based on the information they found, without outside recommendations (59%). The majority of the patients used patient brochures about CLL as an important source of information (54%), followed by specific lectures (34%) or the internet (32%). Conclusion  Our data show that patients with CLL use a wide range of CAM, among them potentially harmful methods. Rational, evidence-based medical information about the effects and risks of CAM use should be made available through patient brochures distributed by patient organizations, through information events with lectures, or via the internet.     

Successful treatment of relapsed chronic lymphocytic leukemia with venetoclax in a patient with severe chronic kidney disease

Venetoclax is a promising new drug for relapsed or refractory chronic lymphocytic leukemia (CLL). However, venetoclax use had not been reported in severe chronic kidney disease (CKD) patients. We report the first case of relapsed CLL in a severe CKD patient that was successfully treated with venetoclax.     

氟达拉滨联合环磷酰胺和甲泼尼龙琥珀酸钠治疗慢性淋巴细胞性白血病的疗效观察

目的评价FCP方案(氟达拉滨+环磷酰胺+甲泼尼龙琥珀酸钠)治疗慢性淋巴细胞性白血病(CLL)的疗效和不良反应。方法 25例CLL患者,其中初发14例,难治、复发11例,均采用FCP方案治疗:氟达拉滨50 mg/d第1～3天,环磷酰胺300 mg/d,第1～3天,甲泼尼龙琥珀酸钠40 mg/d,第1～5天;28～30 d为1周期,重复4～6个周期。结果 25例患者均完成4～6个周期化疗,平均4.9个周期。完全缓解(CR)率64%,部分缓解(PR)率28%,总有效率(OR)92%。初治组14例患者OR率100%,CR率为78.6%,PR率为21.4%;复发或难治组患者OR率81.9%,CR率45.5%,PR率36.4%,两组CR率、OR率差异无统计学意义(P>0.05)。主要不良反应为骨髓抑制和感染,均在耐受范围之内,其他不良反应有恶心、呕吐,肝肾功能损害,血糖升高等,经治疗后可以恢复正常。结论 FCP方案治疗CLL疗效确切,不良反应轻,可以作为治疗CLL的首选方案。     

Chronic lymphocytic leukemia/small lymphocytic lymphoma complicated with skin Langerhans cell sarcoma: A case report

BACKGROUNDLangerhans 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 SUMMARYA 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.CONCLUSIONIn this patient, the skin lesion of LCS showed no concomitant CLL/SLL.     

自身免疫性疾病和慢性肝病IgG4增高者血清IgG4／IgG分析

目的：探讨自身免疫性疾病和慢性肝病IgG4增高者血清中IgG4／IgG二组差异,并与健康人群进行比较。方法收集上海市仁济医院南院门诊和住院的自身免疫性疾病患者血清25例,慢性肝病患者伴IgG4增高者血清49例,以健康体检者血清30例作为对照组。利用免疫散射比浊法分别检测上述三组患者血清IgG4和IgG水平,计算IgG4与IgG比值,并分析三组之间血清IgG4水平和IgG4／IgG值的差异。结果与对照组相比,自身免疫性疾病组和慢性肝病伴IgG4增高组IgG4水平均显著升高,IgG4／IgG值均显著升高（P＜0．05）。与慢性肝病伴IgG4增高组相比,自身免疫性疾病组IgG4水平和IgG4／IgG值均显著升高（P＜0．05）。结论本文结果显示自身免疫性疾病患者和慢性肝病伴IgG4增高患者IgG4与IgG水平并非成一定比例增高,IgG4具有含量和比例增高现象,说明IgG4单项检测和IgG4／IgG检测对鉴别自身免疫性疾病和慢性肝病具一定临床价值。     

Concurrent monoclonal gammopathy and systemic lupus erythematosus in a known case of ulcerative colitis: A case report

Our patient had previously been diagnosed with Ulcerative colitis. The clinical manifestations of the patient along with laboratory tests such as anti‐dsDNA and proteinuria were also positive. Therefore, the clinical manifestation was consistent with SLE. In the following work up, monoclonal gammopathy in serum electrophoresis was also detected.     

A case of bone lesion in a patient with relapsed chronic lymphocytic leukemia and review of the literature

Skeletal involvement in CLL is very rare. We present a case of ileum bone lesion during in a patient receiving 5th line of therapy. Despite radiotherapy and salvage therapies, subsequent bone lesions led to a fatal outcome. Further studies on the mechanism by which bone disease develops are currently needed.     

Chronic neutrophilic leukemia complicated with monoclonal gammopathy of undetermined significance: A case report and literature review

BackgroundStudy of the molecular biological characteristics of chronic neutrophilic leukemia complicated with plasma cell disorder (CNL‐PCD) and lymphocytic proliferative disease (CNL‐LPD).MethodsThe clinical data of a patient with chronic neutrophilic leukemia complicated with monoclonal gammopathy of undetermined significance (CNL‐MGUS) in our hospital were reviewed, and the Chinese and/or English literature about CNL‐PCD and CNL‐LPD in PubMed and the Chinese database CNKI in the past 10 years was searched to analyze the molecular biological characteristics of this disease.ResultsA 73‐year‐old male had persistent leukocytosis for 18 months. The white blood cell count was 46.77 × 109/L and primarily composed of mature neutrophils; hemoglobin: 77 g/L; platelet count: 189 × 109/L. Serum immunofixation electrophoresis showed IgG‐λ monoclonal M protein. A CT scan showed splenomegaly. Next‐generation sequencing (NGS) showed that CSF3R T618I, ASXL1 and RUNX1 mutations were positive. It was diagnosed as CNL‐MGUS. We summarized 10 cases of CNL‐PCD and 1 case of CNL‐LPD who underwent genetic mutation detection reported in the literature. The CSF3R mutational frequency (7/11, 63.6%) was lower than that of isolated CNL. The ASXL1 mutations were all positive (3/3), which may represent a poor prognostic factor. The SETBP1 mutation may promote the progression of CNL‐PCD. We also found JAK2, RUNX1, NRAS, etc. in CNL‐PCD.ConclusionsChronic neutrophilic leukemia may be more inclined to coexist with plasma cell disorder. The CSF3R mutation in CNL‐PCD is still the most common mutated gene compared with isolated CNL. Mutations in SETBP1 and ASXL1 may be poor prognostic factors for CNL‐PCD.     

Gamma heavy chain disease in a patient with diabetes and chronic renal insufficiency: diagnostic assessment of the heavy chain fragment

Heavy chain diseases are rare B-cell disorders that are characterized by an overproduction of abnormal and structurally incomplete monoclonal immunoglobulin (Ig) heavy chains and are devoid of light chains. We describe a case of a 62 year-old African-American woman with a long history of poorly controlled type 2 diabetes and subsequent probable diabetic nephropathy, hypertension, and recent onset of peripheral neuropathy involving all extremities. Routine laboratory testing revealed a distinct beta spike by urine protein electrophoresis (UPEP). No serum abnormality was noted on serum protein electrophoresis (SPEP). Serum and urine immunofixation demonstrated an IgG heavy chain protein devoid of any corresponding light chains. IgG subclasses identified IgG1 as the predominant IgG component but when we added all the subclasses, the sum, 683.4 mg/dL, failed to come close to our total IgG of 1,770 mg/dL. Therefore, a urine IgG subclass determination was performed in-house and we identified a subclass 3 gamma chain. In conclusion, we portray a patient with an underlying monoclonal gamma heavy chain disease (HCD) who presented with a complex medical history. The evaluation of IgG subclasses in the context of a HCD may be limited by the capability of the test to recognize the particular IgG fragment.     

核形正常的慢性淋巴细胞白血病13q14缺失的研究

目的研究核形正常的慢性淋巴细胞白血病（CLL）13q14缺失的情况。方法运用位于13q14的序列特异性DNA探针RB1、D13S319、D13S25和间期荧光原位杂交（I-FISH）技术对26例初发的CLL患者进行染色体13q14的检测。结果 26例B-CLL中12例（46.1%）有13q14缺失,阳性细胞率为25.0%～90.0%,其中RB1单独缺失0例,D13S319单独缺失3例（11.5%）,D13S25单独缺失3例（11.5%）;RB1、D13S319、D13S25同时缺失1例（3.9%）,D13S319、D13S25同时缺失有5例（19.2%）。结论 CLL患者13q14缺失区域是不恒定的,而I-FISH是研究13q14缺失准确而快速的方法。     

核形正常的慢性淋巴细胞白血病13q14缺失的研究

目的研究核形正常的慢性淋巴细胞白血病(CLL)13q14缺失的情况。方法运用位于13q14的序列特异性DNA探针RB1、D13S319、D13S25和间期荧光原位杂交(I-FISH)技术对26例初发的CLL患者进行染色体13q14的检测。结果 26例B-CLL中12例(46.1%)有13q14缺失,阳性细胞率为25.0%～90.0%,其中RB1单独缺失0例,D13S319单独缺失3例(11.5%),D13S25单独缺失3例(11.5%);RB1、D13S319、D13S25同时缺失1例(3.9%),D13S319、D13S25同时缺失有5例(19.2%)。结论 CLL患者13q14缺失区域是不恒定的,而I-FISH是研究13q14缺失准确而快速的方法。     

Merkel cell carcinoma on the right calf in association with chronic lymphocytic leukemia: A case report

This study showed a rare case of Merkel cell carcinoma (MCC) with atypical manifestations accompanied by chronic lymphocytic leukemia of B‐cell type that underwent chemotherapy and had poor prognosis. The findings suggest that the physicians should consider MCC when performing diagnosis and assess all possible associated risk factors like neoplasms to achieve good prognosis.     

慢性淋巴细胞白血病13q14缺失的基因检测

目的研究慢性淋巴细胞白血病（CLL）13q14缺失的情况。方法运用位于13q14的序列特异性DNA探针RB1、D13S319、D13S25和间期荧光原位杂交（I-FISH）技术对26例初发的B细胞CLL患者进行染色体13q14的检测。结果26例B．CLL中14例（53．8％）有13q14缺失,阳性细胞率为30．0％～90．0％,其中RB1缺失2例（7．7％）,D13S319缺失11例（42．3％）,D13S25缺失13（50．0％）RB1、D13S319、D13S25同时缺失2例,D13S319、D13S25同时缺失有8例（30．7％）。结论CLL患者13q14缺失区域是不恒定的。     

SARS CoV 2 infection in chronic myelogenous leukemia: Severe hematological presentation

Infection with SARS-CoV-2, the cause of coronavirus infectious disease-19 (COVID-19), has caused a pandemic. Few data are available about the risk of COVID-19 infection in persons with hematological cancer, but controversy whether these persons have the same clinical signs and outcomes. We describe a case of life‐threatening COVID-19 infection complicated by severe anemia in patients affected also by chronic myelogenous leukemia. The screening for RBC antibodies and the direct antiglobulin test (DAT) turned positive. The identification of the antibodies, showed the presence of an alloantibody with anti-Lewis b specificity, which was reactive at room temperature, in the anti-human globulin phase (AGH) and with papain-treated red blood cells. At the same time hemophagocytic lymphohistiocytosis (HLH), on the basis of major laboratory findings including hyperferritnemia, increase of triglicerides levels and according to the HLH score was suspected. Patients received antiviral therapy, steroids and intravenous immunoglobulins. Hemolysis resolved and ferritin dramatically decreased after administration of Ig and a Afull recovery was achieved after viral infection resolution.This case highlights the novel and multifaceted hematological findings during sever COVID 19 infection. COVID 19-related pneumonia is mediated by hyper activation of effector T cells and excessive production of inflammatory cytokines, such as IL-6, IL-1, interferon-gamma, and TNF. This inflammatory process called "cytokine storm" is a life-threatening complication of COVID 19 infection. In this case severe immunohematological consequences are reported for the first time and recognition of this complications are probably underestimated.     

Targeting chronic lymphocytic leukemia cells in the tumor microenviroment: A review of the in vitro and clinical trials to date

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.     

The FcɛR2/CD23 antigen: A hallmark of chronic lymphocytic leukemia B cells

Summary The effect of different stimuli on the expression of the low-affinity receptor for the Fc fragment of IgE (FcɛR2/CD23) on peripheral blood B cells from patients with chronic lymphocytic leukemia (CLL) was investigated. CLL B cells cultured for 3 days in medium alone showed a progressive decrease of the FcɛR2/CD23 expression, while the addition to the cell cultures of IgE or interleukin-4 had a slackening effect on the decrease of the FcɛR2/CD23. In contrast, in the presence of interferon-γ the proportion of FcɛR2/CD23⁺ cells was more rapidly reduced compared to CLL B cells cultured in medium alone. Stimulation of CLL B cells withStaphylococcus aureus Cowan I (SAC) bacteria, which are able to enhance the expression of FcɛR2/CD23 on normal B cells, induced a rapid loss of the FcɛR2/CD23 from CLL B cells.