Chronic Lymphocytic Leukemia Presenting as Bilateral Periorbital Edema Treated With Low-dose Radiation Therapy.

Ocular manifestations in chronic lymphocytic leukemia (CLL) have been reported in 30% to 40% of patients and may be a result of direct tissue infiltration, concomitant blood dyscrasias, or a result of therapeutic intervention. Leukemia cutis, defined as infiltration of the epidermis or dermis by neoplastic lymphocytes, is rare. Herein, we present a case report of a patient with leukemia who presented with periorbital edema and ecchymosis. This is the first known case to date of periorbital CLL successfully treated with low-dose radiation therapy (4 Gy in 2 fractions). Clinicians should be aware of the possibility of ocular involvement from CLL, given the importance of prompt diagnosis and treatment.

Cutaneous B-cell chronic lymphocytic leukaemia resembling a granulomatous rosacea.

B-cell chronic lymphocytic leukemia (B-CLL) is a low-grade lymphoproliferative disease. Cutaneous involvement of B-CLL is limited and, in most cases, it represents non-specific manifestations related to an impaired immune system. Leukemic skin infiltrates (leukemia cutis) occur in 4-20% of patients. Herein we report the case of a 65-year-old woman with B-CLL presenting with papular, nodular, and plaque skin infiltrates affecting the nose, mimicking granulomatous rosacea. We discuss several aspects of rare cutaneous manifestations of B-CLL involving the face.

Chronic lymphocytic leukemia with central nervous system involvement: report of two cases with a comprehensive literature review.

Central nervous system (CNS) involvement is a rare complication of chronic lymphocytic leukemia (CLL) with varied outcomes. We contribute two additional cases of CLL with CNS involvement. The clinical course and response to treatment are described. All 78 previously reported cases of CLL with CNS involvement are presented in this comprehensive review of the literature. CNS involvement of CLL is a rare complication that does not seem to correlate with any evident risk factors. Resolution of CNS symptoms can often be accomplished with intrathecal chemotherapy or irradiation. Early detection and treatment may result in better outcomes in this rare complication.

Hodgkin's lymphoma variant of Richter's syndrome.

Chronic lymphocytic leukemia/small lymphocitic lymphoma (CLL/SLL) is low-grade malignant lymphoprolipheration, that has tendency to convert to a higher-grade neoplasm over time. More common is the development of a diffuse large cell lymphoma or transformation into prolymphocytic cell population. In rare cases, 0.1-0.5% of patients develop multiple myeloma or Hodgkin's disease. We present 65-year-old female with Hodgkin's variant of Richter's syndrome. On the basis of clinical simptoms, cytological, hystological and immunohistological finding in April 2008 CLL/SLL were diagnosed. The patient was treated with 8 courses of R-CHOP. After 10 months, FNA of the one of the enlarged lymph node on the neck was performed. The diagnosis was Hodgkin's disease. Immuno-hystological studies of the lymph node was consistent with type I Hodgkin's type of Richter's syndrome. Patient was treated with 3 courses of ABVD and radiotherapy.

Radioisotopic localization of (90)Yttrium-ibritumomab tiuxetan in patients with CD20+ non-Hodgkin's lymphoma.

PURPOSE: (90)Yttrium-ibritumomab-tiuxetan (Zevalin) is an effective treatment for relapsed or refractory low-grade, follicular, or transformed B-cell NHL. The purpose of this study is to assess whether tissue and cellular localization of (90)Y-ibritumomab-tiuxetan determined by autoradiography and radioactivity localized to tumor tissue might enhance our understanding of the mechanism of action of radioimmunotherapy. METHODS: Eight eligible patients had CD20+ NHL, a bulky peripheral lymph node, and were scheduled for (90)Y-ibritumomab-tiuxetan treatment. 2-Deoxy-2-[F-18]fluoro-D: -glucose-positron emission tomography/computed tomography (FDG-PET/CT) was performed prior to treatment and at 12 weeks after therapy for assessment of response. Bone marrow, lymph node, and blood samples were collected 114 +/- 3 h after 14.8 MBq/kg (90)Y-ibritumomab-tiuxetan and processed for histology, scintillation counting, and microscopic autoradiography. RESULTS: Pericellular membrane localization of (90)Y-ibritumomab-tiuxetan to lymphoma cells was observed by autoradiography in the involved areas of lymph node with absence of significant localization in histologically normal sections of bone marrow. Pericellular radioactivity and the highest quantitative radioactivity were observed in lymph node samples of responding patients. CONCLUSIONS: (90)Y-ibritumomab-tiuxetan localizes to the surface membrane of CD20+ lymphoma cells in affected lymph nodes. The patients with the highest quantitative concentration of radioactivity to the lymph node as determined by scintillation counting were observed to have a clinical and FDG-PET/CT response.

Unusual presentation for small lymphocytic lymphoma: Case report of a man with bilateral ear involvement and review of the literature.

INTRODUCTION: Ear involvement by non-Hodgkin lymphoma is quite rare and can be mistaken for other common lesions encountered in otolaryngology. The literature on this subject is also limited. CASE SUMMARY: A 45-year-old man with bilateral ear nodules that progressed over two years. Biopsy of the right ear revealed a B-cell small lymphocytic lymphoma (SLL). The patient responded to radiotherapy well. He received an additional dose two months after the initial treatment because of a remaining nodularity on the right earlobe. After several months, he presented a new lesion on his nasal tip, for which a biopsy confirmed a lymphoma relapse. The patient was managed with oral prednisone and low-dose radiation with a favourable response. DISCUSSION: This case highlights the importance of including lymphoma in the differential diagnosis of ear lesions from an otolaryngology perspective. A biopsy of any lesion or nodule with an atypical course should be considered for appropriate diagnosis and management.

Incidence of central nervous system involvement in chronic lymphocytic leukemia and outcome to treatment.

Leptomeningeal involvement in patients with CLL is relatively rare and the prognosis is usually considered to be poor. The authors reviewed all CLL patients treated in a tertiary referral center to assess the incidence and outcome of leptomeningeal involvement (LI) in CLL. They found an incidence of 1-2% of LI. Most of the patients with LI had a longterm survival, despite failure to clear the cerebrospinal fluid from tumor cells.

In vitro and in vivo evaluation of direct rhenium-188-labeled anti-CD52 monoclonal antibody alemtuzumab for radioimmunotherapy of B-cell chronic lymphocytic leukemia.

Alemtuzumab (Campath, Berlex) is a humanized IgG1 rat monoclonal antibody directed against the cell surface CD52 antigen, found on lymphocytes and monocytes. It is being developed for the treatment of chronic lymphocytic leukemia (CLL), autoimmune disease and for the prevention of transplant rejection. This study focused on synthesis, quality control, in vitro evaluation and biodistribution of (188)Re-labeled alemtuzumab for radioimmunotherapy of B-cell CLL. (188)Re-alemtuzumab was synthesized using a direct radiolabeling method. Reduction of the intramolecular disulfide bonds of the antibody was performed with tris-(carboxyethyl)-phosphine (Pierce), using a 1:60 molar excess. Reaction took place at room temperature for 20 min. A PD-10 desalting column was used to purify the reduced antibody from excess phospine. Complexation and transchelation of (188)ReO(4)(-) was achieved using sodium gluconate as weak chelator and SnCl(2) as reducing agent. Quality control was done using instant thin-layer chromatography. Binding assays were performed on a CD52-positive cell line (HuT-78). Female NMRI mice were injected intravenously with 20 microg radiolabeled alemtuzumab and killed at preset time intervals for biodistribution studies. Tissues were dissected, weighed and counted for determination of radioactivity. Data were expressed as percentage injected activity per gram of tissue (% IA/g tissue) or as percentage injected activity (% IA). (188)Re-alemtuzumab was prepared achieving high radiochemical yields. Labeling efficiency of more than 95% can be obtained using optimal reaction conditions. (188)Re-alemtuzumab showed good in vitro stability, remaining intact at 24 h after radiolabeling. In mice, (188)Re-alemtuzumab showed high uptake in the blood (25.10+/-1.36% IA at 1 h p.i.), followed by a biexponential clearance (t(1/2alpha)=4.790 h and t(1/2beta)=55.45 h). Increased uptake was observed in kidneys and heart (9.29+/-0.46% IA/g in kidneys and 6.10+/-1.82% IA/g in heart at 1 p.i.). The highest absorbed radiation dose was received by the kidneys (0.159-3.26 mGy/MBq) and heart wall (0.0705-0.132 mGy/MBq). The predicted radiation dose for the total body was in the range of 0.0459-0.0529 mGy/MBq. The effective dose for the human reference adult was estimated to be approximately 0.0486-0.195 mSv/MBq. (188)Re-alemtuzumab can be prepared with high radiochemical yield and purity and showed good in vitro behavior and favorable biodistribution. Therefore, (188)Re-alemtuzumab would be an ideal candidate for radioimmunotherapy of chronic lymphocytic leukemia.

Bilateral infiltrative disease of the extraocular muscles: a rare clinical presentation of early stage chronic lymphocytic leukemia.

Orbital involvement in chronic lymphocytic leukemia (CLL) is highly unusual and most commonly involves hemorrhage or soft tissue infiltration in advanced disease. We report a case of rapid onset bilateral orbital muscle infiltration as the presenting feature of early stage CLL. In addition, we demonstrate clinico-pathological correlation with an identical chronic B-cell lymphocytic infiltrate in both orbit and bone marrow, with good response of the orbital disease to local radiotherapy.

Cytokine release syndrome after radiation therapy: case report and review of the literature.

BACKGROUND: Cytokine release syndrome (CRS) has been reported after immunologic manipulations, most often through therapeutic monoclonal antibodies. To our knowledge, CRS after radiation therapy (RT) for cancer has not been reported before. The development of unusual clinical signs and symptoms after RT led us to investigate the possibility of CRS after RT and review the medical literature on this topic. CASE PRESENTATION: A 65 year-old man with untreated chronic lymphocytic leukemia and recurrent, metastatic Merkel cell carcinoma undergoing anti-programmed death 1 (PD1) immunotherapy was referred for palliative RT to sites of progressing metastases. Within hours of each weekly dose of RT, he experienced fever, tachycardia, hypotension, rash, dyspnea, and rigors. Based on clinical suspicion for CRS, blood cytokine measurements were performed 1 h after the second and third dose of RT and demonstrated tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) levels approximately ten-fold higher than normal. These were near normal immediately prior to the third dose of RT, and resolved to normal levels 3 weeks after RT. He experienced rapid regression of irradiated tumors, with development of new sites of metastases soon thereafter. A literature review revealed no clinical cases of CRS after RT for cancer. CONCLUSIONS: RT during anti-PD1 immunotherapy in a patient with underlying immune dysfunction appeared to be the putative mediator of an immune process which yielded significant increases in pro-inflammatory cytokines, and produced the clinical symptoms meeting the definition of grade 3 CRS. This case demonstrates the capability of RT to elicit immune-related adverse events.

Venous thromboembolism in chronic lymphocytic leukemia: a Danish nationwide cohort study.

Venous thromboembolism (VTE) is associated with inferior survival in cancer patients. The risk of VTE and its effect on survival in chronic lymphocytic leukemia (CLL) patients remains unclear. The present study investigated the impact of patient-related factors, CLL prognostic markers, and CLL treatment on the risk of VTE and assessed overall survival relative to VTE. All patients in the Danish National CLL Registry (2008-2015) were followed from the date of CLL diagnosis to death, VTE, emigration, or administrative censoring. Hazard ratios (HRs) were estimated using Cox models, and second primary cancers and anticoagulation treatment were included as time-varying exposures. During a median follow-up of 2.6 years, 92 VTEs occurred among 3609 CLL patients, corresponding to a total incidence rate of 8.2 VTEs per 1000 person-years (95% confidence interval [CI], 6.7-10.1). A history of VTE or second primary cancer was associated with HRs of VTE of 5.09 (95% CI, 2.82-9.17) and 3.72 (95% CI, 2.15-6.34), respectively, while ß2-microglobulin >4 mg/L, unmutated immunoglobulin HV and unfavorable cytogenetics had lower HRs. CLL patients with VTE had marginally higher mortality, which was most pronounced among patients <60 years of age (HR, 7.74; 95% CI, 2.12-28.29). Our findings suggest that markers of unfavorable CLL prognosis contribute to an increased risk of VTE; however, previous VTE or a second primary cancer is more strongly associated with the risk of VTE than any CLL-specific marker. Focusing attention on this preventable complication may improve survival in young CLL patients.

Autologous stem cell transplantation for chronic lymphocytic leukemia.

Autologous stem cell transplantation (ASCT) has been intensively investigated for treatment of patients with chronic lymphocytic leukemia (CLL) during recent years. To assess the potential therapeutic value of ASCT for CLL, the present article aims at answering the following crucial questions: (1) Does ASCT have curative potential? (2) What is the therapeutic potential of ASCT in terms of disease control in relation to toxicity? (3) What is the role of ASCT in the current arsenal of CLL treatment modalities? Evidence from clinical and minimal residual disease (MRD) studies suggests that ASCT has curative potential in only a few patients, if any. Nevertheless, ASCT might be capable of prolonged disease control even in CLL with poor-risk features. Uncontrolled prospective studies have indicated the superiority of ASCT over alkylator and fludarabine monotherapy but not necessarily over purine analogue cyclophosphamide or antibody combinations. A significant risk of secondary neoplasms, in particular myelodysplasias, has to be taken into account. Therefore, ASCT cannot be considered as standard treatment for CLL and should be performed only in the context of clinical trials.

Lichenoid paraneoplastic pemphigus in the absence of detectable antibodies.

Paraneoplastic pemphigus (PNP) has been described as an antibody-mediated mucocutaneous disease occurring almost exclusively in patients with lymphocytic neoplasms. We describe 4 patients with the clinical features of the lichenoid variant of PNP in the absence of detectable autoantibodies. On the basis of these findings, we conclude that the spectrum of PNP likely includes patients with disease predominantly or exclusively mediated by cytotoxic T cells rather than autoantibodies. The pathophysiology and range of PNP disease are likely more complex than was initially believed.

Primary cutaneous B-cell lymphoma (low-grade, non large cell).

A 43-year-old man presented with erythematous, indurated plaques on the scalp in the setting of a 16-year history of recurrent cutaneous tumors of the head and trunk. Clinical and histopathologic findings were consistent with a diagnosis of primary cutaneous B-cell lymphoma. Laboratory data and computed tomography imaging of the chest, abdomen, and pelvis failed to show an associated systemic lymphoma. Primary cutaneous B-cell lymphomas are a heterogenous group of lymphomas that primarily involve the skin but have variable clinical, histopathologic, and immunologic phenotypes. Successful treatment for most localized subtypes consists of surgical excision and radiation therapy. Rituximab, a chimeric monoclonal antibody that binds the B-cell-specific antigen CD20, has shown promise in treating a number of primary cutaneous B-cell lymphomas.

[Splenic irradiation: apropos of 8 cases. Clinical indications and literature review]. / Radioterapia esplénica: a próposito de 8 casos. Indicaciones y revisión de la literatura.

Clinical indications of splenic irradiation in haematological disorders include the irradiation in lymphoproliferative disorders with spleen infiltration, palliative treatment of splenomegaly in malignant diseases like chronic lymphocytic leukaemia or myeloproliferative disorders, with the purpose of relief from abdominal pain associated with capsular enlargement size and decrease cytopenias secundaries to hypersplenism.This paper reports our experience with spleen irradiation in the Hospital General Universitario Gregorio Marañón in the last five years, and analyzes indications, results and toxicity, and an actual review of the literature.

The Role of Radiation in All Stages of Nodular Lymphocytic Predominant Hodgkin Lymphoma.

BACKGROUND: The goal of this study was to assess the survival differences seen in early-stage and advanced-stage nodular lymphocytic predominant Hodgkin lymphoma (NLPHL) based on treatment modality. PATIENTS AND METHODS: The National Cancer Database was queried to identify patients diagnosed with NLPHL between 2004 and 2012. Overall survival (OS) was determined using univariate and multivariate Cox regression analysis. Kaplan-Meier and log-rank analysis were used to estimate differences in OS between treatment groups. RESULTS: A total of 1968 patients were identified for analysis, consisting of stage I (40.4%), stage II (29.3%), stage III (22.3%), and stage IV (8.0%) disease. The median age of patients was 46 years. The following factors were predictive of radiotherapy (RT) omission in treatment: increasing age, black race, Medicare insurance, chemotherapy use, stage II to IV disease, and the presence of B-symptoms. On survival analysis, RT was associated with prolonged OS in all stages of NLPHL (50.1 vs. 42.4 months; P < .01). The OS benefit of RT persisted on multivariate analysis (hazard ratio, 0.37; P < .01). On subset analysis, RT was associated with prolonged OS in early disease (49.8 vs. 45.5 months; P < .01), whereas a trend towards an OS benefit was observed in advanced-stage (54.1 vs. 39.6 months; P = .06) NLPHL. Radiotherapy was also associated with prolonged OS among patients with B-symptoms (49.0 vs. 42.6 months; P < .01). CONCLUSION: The use of RT in NLPHL is less likely among those with advanced-stage disease and B-symptoms. However, we found RT to be associated with prolonged OS in all stages of NLPHL, including those with B-symptoms.

Idelalisib may have the potential to increase radiotherapy side effects.

INTRODUCTION: Idelalisib is approved for the treatment of relapsed chronic lymphocytic leukemia together with Rituximab and for monotherapy of follicular B-cell non-Hodgkin's lymphoma and small lymphocytic lymphoma. It is a potent and selective phosphatidylinositol 3-kinase-δ (PI3K-δ) inhibitor. PI3K-δ primarily is expressed in B-cells and prevents effectively proliferation in malignant B-cells. METHODS: We provide a detailed report on treatment history and photo documentation of acute adverse effects of radiation therapy with simultaneous Idelalisib medication in one case of B-CLL. Radiosensitivity tests were performed for the index patient under Idelalisib and after the addition of Idelalisib to healthy individuals' blood. Radiosensitivity in human lymphocytes was analyzed with a three color in situ hybridization assay. Primary skin fibroblasts were studied after a treatment with Idelalisib for apoptosis, necrosis and cell cycle using flow cytometry. DNA double-strand break repair was analyzed by γH2AX immunostaining. RESULTS: The index patient presented a strong grade 2 radiodermatitis and grade 3 mucositis after irradiation with 20 Gy and a simultaneous intake of Idelalisib. Irradiations without Idelalisib medication were well tolerated and resulted in not more than grade 1 radiodermatitis. The index patient under Idelalisib had a radiosensitivity of 0.62 B/M which is in the range of clearly radiosensitive patients. A combined treatment of lymphocytes with 2 Gy and 10 nmol/l Idelalisib showed a tendency to an increased radiosensitivity. We found a clear increase of apoptosis as a result of the combined treatment in the Idelalisib dose range of 1 to 100 nmol/l compared to solely irradiated cells or solely Idelalisib treated cells (p = 0.05). CONCLUSION: A combined Idelalisib radiotherapy treatment has an increased risk of side effects. However, combined therapy seems to be feasible when patients are monitored closely.

In vitro screening for synergism of high-linear energy transfer 213Bi-radiotherapy with other therapeutic agents for the treatment of B-cell chronic lymphocytic leukemia.

BACKGROUND: External beam radiotherapy and beta-radioimmunotherapy (RIT) are effective treatments for lymphoid malignancies. The development of RIT with alpha-emitters is attractive, owing to the high (LET) nature and short path length of alpha particles allowing for higher tumor cell kill and lower toxicity to healthy tissues. OBJECTIVES: The aim of this study was to assess the response of B-Cell chronic lymphocytic leukemia (B-CLL) cells in vitro after treatment with chemotherapy (cisplatin, fludarabine, doxorubicin, or vincristine) or other pharmaceuticals (colchicine, simvastatin, or cyclosporin A) in combination with (60)Co-gamma or (213)Bi-alpha-irradiation. METHODS: (213)Bi was eluted from a (225)Ac generator. Apoptosis was scored by flow cytometric analysis of the cells stained with Annexin-V and 7 amino actinomycin D. Metabolic activity was assessed by a MTT assay. RESULTS: The response induced by alpha- irradiation is systematically higher than the response induced by gamma-irradiation. The combination of drug treatment with alpha-irradiation induced a systematic, higher response, compared to treatment with drugs alone, even for the highest concentrations used. For all the drugs used in this study, synergism or additivity was demonstrated for the combination of drugs and radiotherapy with a stronger effect for alpha-particles. CONCLUSIONS: The results of this in vitro study highlight a potential benefit of alpha-irradiation in combination with the drugs considered in this study.