Asymptomatic Chronic Lymphocytic Leukemia Research Articles

Vitamin D supplement for patients with early-stage chronic lymphocytic leukemia is associated with a longer time to first treatment

AbstractLow levels of vitamin D are associated with a shorter time to first treatment (TTFT) and inferior overall survival in patients with chronic lymphocytic leukemia (CLL). But whether vitamin D supplement affects the clinical course of patients with CLL, remains an open question. In this study, we aimed to retrospectively explore the clinical benefit of vitamin D supplement or one of its analogs, on TTFT and treatment-free survival (TFS) in a large cohort of patients with asymptomatic CLL, who were under watch-and-wait approach. Among the 3474 patients included in the study, 931 patients (26.8%) received either vitamin D supplement or its analog, for a minimum of 6 months. We found that vitamin D supplement was statistically significant for longer TTFT in the young cohort (age ≤65) and was associated with a longer TFS for all ages (P = .004). Among non–vitamin-D users, the median TFS was found to be 84 months, whereas among vitamin D supplement users the median TFS extended to 169 months. In conclusion, our long-term retrospective study demonstrates that the administration of vitamin D to patients with CLL in a watch-and-wait active surveillance is significantly associated with a longer TFS (in any age) and a longer TTFT among young patients (age ≤65). A prospective clinical trial is needed to validate results.

Melanoma and CLL co-occurrence and survival: role of KC history

BackgroundSurvival following melanoma and chronic lymphocytic leukemia (CLL) have both been individually associated with previous history of non-melanoma skin cancers (specifically keratinocyte carcinomas [KC]). Furthermore, melanoma and CLL have been reported to occur within the same patients. The survival experience of patients with both cancers is understudied, and the role of history of KC is unknown. Additional research is needed to tease apart the independent associations between KC and CLL survival, KC and melanoma survival, and the co-occurrence of all three cancers.MethodsA retrospective cohort study was conducted among patients who were diagnosed with melanoma and/or CLL at a comprehensive cancer center between 2008 and 2020. Multivariable Cox regression models were used to examine the association between history of KC and survival following melanoma and/or CLL with careful consideration of calendar year of diagnosis, treatment regimens and other risk factors. A nested case–control study comparing patients with both CLL and melanoma to those with only CLL or only melanoma was conducted to compare blood parameters across the three groups.ResultsA time-dependent association was observed between history of KC and favorable melanoma survival within 4 years following diagnosis and poorer survival post 7 years after melanoma diagnosis. History of KC was not significantly associated with survival following the diagnosis of CLL, after adjustment for clinical factors including historical/concurrent melanoma. Patients with co-occurring melanoma and CLL tended to be diagnosed with melanoma first and had elevated blood parameters including white blood cell and lymphocyte counts as compared with patients who were diagnosed with only melanoma.ConclusionsHistory of KC was an independent predictor of survival following melanoma but not of CLL. Additional studies are needed to determine if blood parameters obtained at the time of melanoma diagnosis could be used as a cost-effective way to identify those at high risk of asymptomatic CLL for the promotion of earlier CLL diagnosis.

How Do We Place Monoclonal B-cell Lymphocytosis in the Context of Early, Asymptomatic Chronic Lymphocytic Leukemia?

How Do We Place Monoclonal B-cell Lymphocytosis in the Context of Early, Asymptomatic Chronic Lymphocytic Leukemia?

Trends in Disease Burden of Chronic Lymphocytic Leukemia at the Global, Regional, and National Levels From 1990 to 2019, and Projections Until 2030: A Population-Based Epidemiologic Study.

BackgroundThe prognosis of chronic lymphocytic leukemia (CLL) has been improved dramatically, but there are limited studies focusing on CLL disease burden on a global scale. We aimed to evaluate the accurate assessment of the disease burden of CLL that may provide more detailed epidemiological information for rational policies.MethodsThe main source of the data was the Global Burden of Disease (GBD) study 2019. Incident cases, death cases, disability-adjusted life years (DALYs), and their corresponding age-standardized rates (ASRs) from 1990 to 2019 were used to describe the burden of CLL. Data about attributable risk factors were also extracted and analyzed. Bayesian age-period-cohort (BAPC) models were used to assess and project the incidence and mortality rates till 2030.ResultsGlobally, the incidence of CLL had been increasing. Deaths and DALYs decreased slightly. The burden of death and DALY is affected by socio-demographic index (SDI). The incidence rate, death rate, and DALY rate of CLL increased significantly with age. Male-to-female ratios of incidence rates varied in different SDI quintiles. Smoking, high body mass index, and occupational exposure to benzene or formaldehyde were the potential risk factors related to CLL. Global ASIRs might tend to increase until 2030, while ASDR would decrease until 2030.ConclusionThe disease burden of CLL decreased in higher SDI countries but increased in lower ones. Strategies for early detection of asymptomatic CLL, development of novel drugs, and measures against attributable factors should be implemented to combat CLL burden.

The CLL12 trial: ibrutinib vs placebo in treatment-naïve, early-stage chronic lymphocytic leukemia

AbstractObservation is the current standard of care for patients with early-stage asymptomatic chronic lymphocytic leukemia (CLL), as chemotherapy-based interventions have failed to prolong survival. We hypothesized that early intervention with ibrutinib would be well tolerated and lead to superior disease control in a subgroup of early-stage patients with CLL. The phase 3, double-blind, placebo-controlled CLL12 trial randomly assigned asymptomatic, treatment-naïve Binet stage A CLL patients at increased risk of progression in a 1:1 ratio to receive ibrutinib (n = 182) or placebo (n = 181) at a dose of 420 mg daily. At a median follow-up of 31 months, the study met its primary endpoint by significantly improving event-free survival in the ibrutinib group (median, not reached vs 47.8 months; hazard ratio = 0.25; 95% confidence interval = 0.14-0.43, P < .0001). Compared with placebo, ibrutinib did not increase overall toxicity, yielding similar incidence and severity of adverse events (AEs). The most common serious AEs were atrial fibrillation, pneumonia, and rash in the ibrutinib group, and basal cell carcinoma, pneumonia, and myocardial infarction in the placebo group. Ibrutinib-associated risk for bleeding (33.5%) was decreased by prohibiting the use of oral anticoagulants through an amendment of the study protocol and by avoiding CYP3A4 drug–drug interactions. Ibrutinib confirms efficacy in CLL patients at an early stage with an increased risk of progression. However, the results do not justify changing the current standard of “watch and wait.” This trial was registered at www.clinicaltrials.gov as #NCT02863718.

Comparison of four prognostic scoring system in patients with early asymptomatic chronic lymphocytic leukemia patients

目的比较四种预后评分系统预测Binet A期中国慢性淋巴细胞白血病（CLL）患者诊断到治疗时间（TTFT）的预后评估价值。方法回顾性分析南京医科大学第一附属医院（浦口慢淋中心）2009年6月至2020年1月诊断的110例Binet A期CLL患者的基线临床资料，采用无症状早期CLL国际预后评分（IPS-E）、CLL国际预后指数评分（CLL-IPI）、CLL1预后评分模型（CLL1-PM）与巴塞罗那预后评分（Barcelona-Brno）模型对患者进行危险度分层和预后评估。结果110例Binet A期CLL患者中位年龄58（25～84）岁，中位随访时间35（4～189）个月，其中57例（51.8％）患者因病情进展达到治疗指征启动治疗。对患者年龄、Rai分期、淋巴细胞绝对计数（ALC）、淋巴结大小、淋巴细胞倍增时间（LDT）、β2-微球蛋白、IGHV突变状态、TP53缺失和（或）突变、11q缺失等9个因素进行Log-rank检验，其中RaiⅠ～Ⅲ期、ALC>15×109/L、淋巴结≥1 cm、β2-微球蛋白>3.5 mg/L、IGHV无突变、TP53缺失和（或）突变、11q缺失是影响TTFT的独立危险因素。使用一致性指数（C-index）和赤池信息准则（AIC）对上述模型进行预后评估效能评价，其中CLL1-PM C-index＝0.736，AIC＝777；CLL-IPI C-index＝0.722，AIC＝933；IPS-E C-index＝0.683，AIC＝1004；Barcelona-Brno C-index＝0.663，AIC＝986。结论四种预后评分模型均具有预测TTFT的效能。IPS-E因纳入指标的临床可及性高，价格较低，可作为指导临床检测的理想工具。对于完善FISH及二代测序检查的患者，使用CLL-IPI或CLL1-PM可进行更为全面的预后评价。

Allogeneic Bone Marrow-Derived Mesenchymal Stem Cell Safety in Idiopathic Parkinson's Disease.

ABSTRACTBackgroundNeuroinflammation plays a key role in PD pathogenesis, and allogeneic bone marrow–derived mesenchymal stem cells can be used as an immunomodulatory therapy.ObjectiveThe objective of this study was to prove the safety and tolerability of intravenous allogeneic bone marrow–derived mesenchymal stem cells in PD patients.MethodsThis was a 12‐month single‐center open‐label dose‐escalation phase 1 study of 20 subjects with mild/moderate PD assigned to a single intravenous infusion of 1 of 4 doses: 1, 3, 6, or 10 × 106 allogeneic bone marrow–derived mesenchymal stem cells/kg, evaluated 3, 12, 24, and 52 weeks postinfusion. Primary outcome safety measures included transfusion reaction, study‐related adverse events, and immunogenic responses. Secondary outcomes included impact on peripheral markers, PD progression, and changes in brain perfusion.ResultsThere were no serious adverse reactions related to the infusion and no responses to donor‐specific human leukocyte antigens. Most common treatment‐emergent adverse events were dyskinesias (20%, n = 4) with 1 emergent and 3 exacerbations; and hypertension (20%, n = 4) with 3 transient episodes and 1 requiring medical intervention. One possibly related serious adverse event occurred in a patient with a 4‐year history of lymphocytosis who developed asymptomatic chronic lymphocytic leukemia. Peripheral inflammation markers appear to be reduced at 52 weeks in the highest dose including, tumor necrosis factor‐α (P < 0.05), chemokine (C‐C motif) ligand 22 (P < 0.05), whereas brain‐derived neurotrophic factor (P < 0.05) increased. The highest dose seems to have demonstrated the most significant effect at 52 weeks, reducing the OFF state UPDRS motor, −14.4 (P < 0.01), and total, −20.8 (P < 0.05), scores.ConclusionA single intravenous infusion of allogeneic bone marrow–derived mesenchymal stem cells at doses of 1, 3, 6, or 10 × 106 allogeneic bone marrow–derived mesenchymal stem cells/kg is safe, well tolerated, and not immunogenic in mild/moderate PD patients. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Effects of Green Tea on Various Types of Indolent Low Grade B-Cell Lymphomas

Low grade B cell neoplasms, such as chronic lymphocytic leukemia (CLL), usually are asymptomatic when diagnosed and undergo close observation. Many patients with low grade B cell lymphomas and leukemias (LGBCL) appreciate reassurance that not treating at time of diagnosis is the appropriate management. Society has long focused on diet and lifestyle changes as an alternative to medication; however, there is limited data to which these changes can assist with hematologic disorders. Green tea (GT) has been studied in regard to its effects on longevity and health. A cohort study followed 52,000 adults over 13 years and found that the frequency of GT consumption was inversely associated with risk of total hematologic neoplasms (Takada M, et al., 2019). There are several other studies that report key oncologic pathways are disrupted by a compound found in GT called epigallocatechin-gallate (EGCG) (Farooqi A, et al., 2020). Following a case series publication by Dr. Shanafelt, the National Cancer Institute sponsored clinical trials through the Mayo Clinic, evaluating EGCG in 42 patients with asymptomatic CLL. Patients received 2000mg EGCG twice daily for 6 months. Results showed 69% of patients had a biological response with greater than 20% reduction in absolute leukocyte count (ALC) and/or greater than 30% in reduction in size of the lymph node area utilizing standard assessment criteria (Shanafelt T. et al. 2013). This data encouraged our practice to recommend to patients to drink two bags of GT in steamy hot water daily. We studied 11 patients with indolent CLL, follicular lymphoma (FL), Waldenstrom macroglobulinemia (WM), monoclonal gammopathy of undetermined significance (MGUS), and splenic Marginal zone lymphoma (MZL). No patient was symptomatic. Disease makers were recorded over time during their routine visits for observation. The markers used were ALC for CLL and MZL, standardized uptake value (SUV) on PET scan for lymph node detection for FL, immunoglobulin level as well as monoclonal protein (M-protein) measured by SPEP for MGUS, and IgM and M-protein for WM. One patient with extensive cutaneous plaque psoriasis had routine skin checks. The results were recorded in the electronic health record over varying time periods based on patient presentation and follow up. Six patients with CLL responded to GT, with reductions in ALC. In patient 1, ALC decreased by 37% over 48 months. Patient 2's ALC decreased by 68% over 102 months. Patient 3's ALC decreased by 74% in 96 months. Patient 4 had a drastic increase in ALC from 23,900 to 72,400 over three years before GT. Once starting GT, his ALC plateaued at 72,000 and has remained stable for 65 months. Patient 5 had decrease ALC of 66% over 99 months. Patient 6 with WM had a 79% decrease in IgM over 65 months drinking GT. M-protein decreased by 81%. Patient 7 had a decrease in IgM by 26% and a 24% decrease in M-protein over 36 months. Patient 8 with MGUS had a decrease in IgG by 25% over 77 months. Patient 9 had a decrease in IgG by 23% with M-protein reduction of 43%. Due to compliance issues, duration of therapy was unknown. Patient 10 with ZL had an ALC reduction of 73% over 95 months. Lastly, patient 11 with FL and psoriasis was treated with GT for 23 months. There was a reduction of external iliac and inguinal lymph node SUV by 38% and 83% over 23 months, respectively. It was also noted of a significant improvement of extensive plaque psoriasis during this time on GT (Table 1). The 11 patients highlighted in the practice had improvement in biomarkers and lymphadenopathy during the time they took daily GT. The EGCG study at Mayo Clinic, in which CLL patients took up to 4,000mg of EGCG per day, had significant responses as well as adverse effects including transaminitis. This compares to the population in our study, which includes various types of LGBCL and MGUS that were taking at most 200mg of EGCG per day and had significant responses with no adverse effects. The use of low dose EGCG for inducing clinical improvement of these types of LGBCL and MGUS may be used to delay the onset of starting therapy, thus forestalling immunosuppressive treatment and associated toxicities. Larger randomized control trials involving other forms of indolent LGBCL and MGUS would be significant for the potential of GT being a safe, non-toxic lifestyle change that could benefit patients who do not require aggressive medical therapy for their neoplastic processes. Disclosures No relevant conflicts of interest to declare.

Novel Therapies in Chronic Lymphocytic Leukemia: A Rapidly Changing Landscape

Treatment landscape of chronic lymphocytic leukemia (CLL) has changed since 2014 after the introduction of inhibitors of B-cell receptor signaling pathway (ibrutinib, acalabrutinib, idelalisib and duvelisib) and the inhibitor of the anti-apoptotic protein BCL-2 (venetoclax). In 2019, novel agents were upgraded from being a "great treatment option" to the "preferred choice" for all lines of treatment after number of randomized clinical trials proved their superiority compared to conventional chemoimmunotherapy (CIT) regimens. A growing number of next-generation molecules are in clinical trials with a promise of improved efficacy and less toxicity. This includes agents with expected better safety profile (zanubrutinib, umbralisib, etc.) or more importantly with a potential to overcome the resistance mechanism to early generation agents (ARQ-531, LOXO-305, or vecabrutinib). Early intervention has once again become an active topic of research and, if proven to provide an overall survival benefit, will eliminate the "watch and wait" strategy for asymptomatic CLL patients. Until then, treatment should only be offered to patients who meet the standard treatment indication in standard practice. With our upgraded therapeutic toolbox, there are and will be many unanswered questions. CLL field will need to define the optimal treatment sequence and most effective combinations with a goal of having a time-limited and chemotherapy-free regimen that provides longest remissions and potentially cure. Cellular immunotherapy with chimeric antigen receptor T-cell (CAR-T) may become available for high-risk CLL along with allogeneic stem cell transplant (allo-SCT). Financial toxicity of novel agents especially when used in combination will need to be an important aspect of research in coming years to avoid unnecessary overtreatment of patients. As current prognostic models (CLL-IPI, etc.) were developed and validated in the CIT era, there is ongoing effort to develop new models using clinical and molecular characteristics to accurately define high-risk CLL in the era of novel agents. We all need to keep in mind that access to the novel agents is currently limited to certain developed countries and every effort should be made to make sure patients around the world also benefit from these outstanding drugs.

HLA specificities are associated with prognosis in IGHV-mutated CLL-like high-count monoclonal B cell lymphocytosis.

IntroductionMolecular alterations leading progression of asymptomatic CLL-like high-count monoclonal B lymphocytosis (hiMBL) to chronic lymphocytic leukemia (CLL) remain poorly understood. Recently, genome-wide association studies have found 6p21.3, where the human leukocyte antigen (HLA) system is coded, to be a susceptibility risk region for CLL. Previous studies have produced discrepant results regarding the association between HLA and CLL development and outcome, but no studies have been performed on hiMBL.AimsWe evaluated the role of HLA class I (-A, -B and -C) and class II (-DRB1 and -DQB1) in hiMBL/CLL susceptibility, hiMBL progression to CLL, and treatment requirement in a large series of 263 patients diagnosed in our center with hiMBL (n = 156) or Binet A CLL (n = 107).ResultsNo consistent association between HLA specificities and hiMBL or CLL susceptibility was found. With a median follow-up of 7.7 years, 48/156 hiMBLs (33%) evolved to asymptomatic CLLs, while 16 hiMBLs (10%) and 44 CLLs (41%) required treatment. No HLA specificities were found to be significantly associated with hiMBL progression or treatment in the whole cohort. However, within antigen-experienced immunoglobulin heavy-chain (IGHV)-mutated hiMBLs, which represents the highest proportion of hiMBL cases (81%), the presence of HLA-DQB1*03 showed a trend to a higher risk of progression to CLL (60% vs. 26%, P = 0.062). Moreover, HLA-DQB1*02 specificity was associated with a lesser requirement for 15-year treatment (10% vs. 36%, P = 0.012).ConclusionIn conclusion, our results suggest a role for HLA in IGHV-mutated hiMBL prognosis, and are consistent with the growing evidence of the influence of 6p21 on predisposition to CLL. Larger non-biased series are required to enable definitive conclusions to be drawn.

Vaccination with Dendritic Cells Loaded with Autologous Leukemic Cells in Combination with Low-Dose Lenalidomide Induced Immune Responses in Chronic Lymphocytic Leukemia (CLL) Patients

Background and aim. We have previously demonstrated that immunization with ex-vivo generated autologous dendritic cells loaded with apoptotic tumor cells (Apo-DC) induces specific immune responses in CLL patients especially when combined with GM-CSF and low-dose cyclophosphamide (CTX) (Palma et al, CII 2012). In this study we evaluate the safety and immunogenicity of Apo-DC vaccination in combination with low-dose lenalidomide alone, or in combination with GM-CSF and low-dose CTX in CLL patients. In patients with multiple myeloma, lenalidomide boosted the response to a pneumococcal vaccine (Noonan et al, Clin Ca Res 2012); lenalidomide may thus be a useful adjuvant also with tumor vaccines but has not yet been explored in man. In patients with CLL, lenalidomide has immunomodulatory properties including NK and T cell stimulation, as well as enhanced immunoglobulin production. Lenalidomide also induced a clinical "flare" reaction, upregulated adhesion molecules and facilitated synapse formation between CLL and T cells (Ramsay et al, J Clin Invest 2008; Shanafelt et al, Blood 2013)i.e. effects of advantage in tumor vaccination. We here report on the first results using lenalidomide as an adjuvant in tumor vaccination in man.Methods. Ten patients with slowly progressive but asymptomatic CLL were included. The first five patients were immunized intradermally five times during fourteen weeks with a mean of 16x106 Apo-DCs. Low-dose lenalidomide was given daily as an adjuvant at a dose of 2.5 mg from start of vaccination, for four weeks, and then escalated to 5 mg daily until week 24 (cohort I). The next five patients were treated in the same way but also received 300 mg/m2 CTX at day -3 and GM-CSF sc day 1-4 (cohort II). Clinical and immune effects of the vaccination were evaluated at regular time intervals for 1 year. A vaccine-induced immune response was defined as a ≥ 2-fold increase compared to pre-immunization values in either 3H-thymidine incorporation (proliferation) assay or ELISpot assay as described (Palma et al, CII 2012). Changes in the numbers of lymphocyte subpopulations including regulatory T cells (Tregs) as well as in T-cells expressing activation (CD69, CD137) and regulatory markers (CD103) were also evaluated.Results. To date, the 8 first included patients have completed treatment as planned and passed study week 52. The remaining 2 patients are between study week 24 and 52. No adverse events (AE) > grade 2 have been observed with the exception of one patient who had grade 3 hemolysis (AIHA) at study week 6 (cohort I) and one patient who had grade 4 thrombocytopenia at study week 5 (cohort II). AIHA was treated with steroids and lenalidomide was temporarily withdrawn for 4 weeks. The grade 4 thrombocytopenia required a 10 weeks withdraw of lenalidomide, upon which the thrombocytopenia resolved to grade 1. A decrease in the lymphocyte count fulfilling the criteria for partial response (clinical PR) was seen in 5 patients during lenalidomide treatment (one in cohort I and four in cohort II), but the lymphocyte count increased again to pre-vaccination levels at withdrawal of lenalidomide at week 24. Vaccine-induced immune responses were noted in 4/5 patients in cohort I and in 2/5 patients in cohort II. An inverse correlation between Tregs numbers and proliferation assay values was observed (r = -0.46, p=0.0015) i.e. high proliferative response was associated with low Tregs count. Changes in T cells expressing activation markers (CD69 and CD137) as well as the regulatory marker CD103 were also observed.Summary/conclusions. This is the first study on lenalidomide as an immunomodulatory agent in tumor vaccination. The results indicate that immunization of CLL patients with autologous tumor-loaded DCs combined with low-dose lenalidomide induced specific immune responses in CLL patients. Lenalidomide as a low-dose immune adjuvance had acceptable tolerability. This therapeutic approach should be explored further to define an optimal combination of vaccination schedule, lenalidomide dose and combination with other immunomodulatory agents interfering with the tumor-microenvironment with the aim to induce a potent immune response with a clinical impact. DisclosuresOff Label Use: Lenalidomide is used as an adjuvant in this CLL vaccination study. Österborg:Celgene: DMC memeber of Celgene-initiated phase 3 trials Other.

Changes in the incidence, pattern of presentation and clinical outcome of early chronic lymphocytic leukemia patients using the 2008 International Workshop on CLL guidelines

Objectives: Before 2008, diagnosis of chronic lymphocytic leukemia (CLL) relied on 1996 National Cancer Institute Working Group criteria which required an absolute lymphocyte count of 5.0 × 109/l or higher. The up-dated 2008 International Workshop on CLL (IWCLL) guidelines recommend using the B-cell count as a basis for the diagnosis of CLL and indicate a B-cell threshold of 5.0 × 109/l. The objective of this study was to assess the effects of these changes on the pattern of presentation and clinical outcome of early CLL. Methods: For this purpose we analysed 414 patients with previously untreated, Binet stage A CLL diagnosed between January 2006 and December 2010 and registered prospectively at a national database. Results: After patients were reclassified according to updated 2008 IWCLL guidelines, 130 Rai stage 0 CLL patients were reclassifed as clinical monoclonal B-cell lymphocytosis, resulting in a 31.4% decrease (from 414 to 284) in the diagnosis of early stage CLL. Moreover, a shift towards a more advanced Rai clinical stage under 2008 IWCLL criteria was observed. Finally, the estimated 3-year time to first treatment decreased from 77.2 to 69.9% according to whether 1996 National Cancer Institute Working Group criteria or 2008 IWCLL criteria were used. Conclusion: In conclusion, the 2008 IWCLL guidelines modify the distribution of Rai stage at diagnosis and shorten the time to first treatment in early CLL patients. We expect that these changes might be considered in the interpretation of epidemiologic studies in CLL and in designing clinical trials of early therapeutic intervention in patients with asymptomatic CLL.

Çok Genç Yaşta Kronik Lenfositik Lösemi Tanısı Konulan Asemptomatik Bir Olgunun Sunulması

Chronic lymphocytic leukemia (CLL) is a disease of advanced age with meanage ≥ 65 at diagnosis. In this paper, we aim to present an asymptomatic chronic lymphocytic leukemia case detected at very young age. A 24-year-old otherwise healthy male patient was found to have high white blood cell (WBC) count 46 x 10 9 /l on routine blood tests. Peripheral blood smear was consistent with lymphocytosis with mature looking lymphocytes. A bone marrow biopsy and the flowcytometric immunophenotyping were performed. These findings and the pathological examination were consistent with CLL. To the best of our knowledge, our patient is the third young CLL case in the literature. This patient was diagnosed at an early stage of the disease and was asymptomatic. While the previously reported cases had poor prognosis, our patient did not possess any poor prognostic feature. As a result, although very infrequent, CLL can be diagnosed among young patients with lymphocytosis and should be kept in mind when treating these patients.

Vaccination with dendritic cells loaded with tumor apoptotic bodies (Apo-DC) in patients with chronic lymphocytic leukemia: effects of various adjuvants and definition of immune response criteria.

We previously demonstrated that autologous dendritic cells that have endocytosed apoptotic bodies of chronic lymphocytic leukemia (CLL) cells (Apo-DC) can stimulate antileukemic T cell responses in vitro. In this phase I study, we vaccinated 15 asymptomatic CLL patients at five time points with Apo-DC administered intradermally either alone (cohort I), or in combination with subcutaneous granulocyte-macrophage-colony-stimulating-factor (GM-CSF) (cohort II) or with GM-CSF and intravenous low-dose cyclophosphamide (cohort III). Aim of the study was to evaluate the safety and immunogenicity of Apo-DC alone or in combination with GM-CSF and low-dose cyclophosphamide in CLL patients. All patients completed the vaccination schedule without dose-limiting toxicity. No objective clinical responses were seen. Vaccine-induced leukemia-specific immune responses were evaluated by IFN-γ ELISpot and proliferation assays over a 52 weeks observation period and immune response criteria were defined. According to these criteria, 10/15 patients were defined as immune responders. The frequency of immune-responding patients was higher in cohorts II (3/5) and III (5/5) than in cohort I (2/5). In order to further characterize the induced immune response, estimation of secreted cytokines and CD107-degranulation assay were performed. Clustering of T and CLL cells was observed in CD107-degranulation assay and visualized by confocal microscopy. Additionally, assessment of regulatory T cells (T(regs)) revealed their significantly lower frequencies in immune responders versus non-responders (P<0.0001). Cyclophosphamide did not reduce T(regs) frequency. In conclusion, vaccination with Apo-DC + GM-CSF and cyclophosphamide was safe and elicited anti-CLL immune responses that correlated inversely with T(regs) levels. Lack of clinical responses highlights the necessity to develop more potent vaccine strategies in B cell malignancies.

Subacute herpes simplex virus type 1 encephalitis as an initial presentation of chronic lymphocytic leukemia and multiple sclerosis: a case report

IntroductionHerpes simplex virus type 1 encephalitis presents acutely in patients who are immunocompetent. We report what we believe to be the first published case of a subacute course of herpes simplex virus type 1 encephalitis in a patient with asymptomatic chronic lymphocytic leukemia who subsequently developed multiple sclerosis.Case presentationA 49-year-old Caucasian woman with a history of fever blisters presented to the emergency department with a history of left temporal headache for four weeks, and numbness of the left face and leg for two weeks. A complete blood count revealed white blood cell count of 11,820 cells/mL, with an absolute lymphocyte count of 7304 cells/mL. The cerebrospinal fluid contained 6 white blood cells/μL, 63 red blood cells/μL, 54 mg glucose/dL, and 49 mg total protein/dL. Magnetic resonance imaging of the brain revealed meningoencephalitis and bilateral ventriculitis. Cerebrospinal fluid polymerase chain reaction for herpes simplex virus type 1 was positive, and the patient's symptoms resolved after ten days of treatment with parenteral aciclovir. Incidental findings on peripheral blood smear and flow cytometry testing confirmed chronic lymphocytic leukemia. One month later, she developed bilateral numbness of the hands and feet; a repeat cerebrospinal fluid polymerase chain reaction for herpes simplex virus type 1 at this time was negative. A repeat magnetic resonance imaging scan showed an expansion of the peri-ventricular lesions, and the cerebrospinal fluid contained elevated oligoclonal bands and myelin basic protein. A brain biopsy revealed gliosis consistent with multiple sclerosis, and the patient responded to treatment with high-dose parenteral steroids.ConclusionHerpes simplex virus type 1 encephalitis is a rare presentation of chronic lymphocytic leukemia. Our patient had an atypical, subacute course, presumably due to immunosuppression from chronic lymphocytic leukemia. This unusual case of herpes simplex virus type 1 encephalitis emphasizes the importance of T cell function in diseases of immune dysregulation and autoimmunity such as chronic lymphocytic leukemia and multiple sclerosis. It raises the question of whether atypical presentations of herpes simplex virus encephalitis warrant deliberations on immunocompetence. The development of multiple sclerosis in our patient so soon after she received treatment for herpes simplex virus type 1 encephalitis raises the possibility that herpes simplex virus type 1 encephalitis in an immunosuppressed patient may trigger multiple sclerosis.

The clinical significance of chromosome 17p deletion in chronic lymphocytic leukemia: A study of 180 consecutive patients

7035 Background: Preliminary data indicate that the presence of chromosome 17p deletion (17p-) by fluorescent in-situ hybridization (FISH) in chronic lymphocytic leukemia (CLL) may be uniquely associated with resistance to standard therapy and dismal survival. Methods: In order to determine the significance of 17p- in CLL in a large cohort, we analyzed the clinical course and treatment outcome of 180 consecutive 17p- CLL pts managed at our center. Results: *PT CHARACTERISTICS. 56 (31%) pts were untreated (UNT), and 124 (69%) had relapsed / refractory (RR) disease. RR pts were more likely to have impaired performance status (PS) (p=0.01), Rai stage 3/4 disease (p<0.01), and elevated β2m (p=0.07). *PROGRESSION TO FIRST THERAPY. For UNT patients with asymptomatic CLL, the 18 month progression to therapy risk was 46%, with 18 pts remaining treatment-free at 7 - 47 months. The 17p- clone was lost spontaneously in 2 pts on follow-up. *RESPONSE TO INITIAL THERAPY. Six UNT pts received rituximab, with 4 (67%) objective responses (OR) and 2 (33%) complete clinical responses (CCR). Twenty-nine UNT pts received fludarabine & rituximab therapy, with 22 (76%) OR and 14 (48%) CCR. All CCR pts tested by FISH showed elimination of their 17p- clone. *RESPONSE TO SALVAGE THERAPY. Results by treatment categories were: rituximab, OR 27% & CCR 0%; alemtuzumab containing regimens, OR 50% & CCR 19%; fludarabine & rituximab therapy, OR 44% & CCR 0%; intensive chemotherapy, OR 20% & CCR 4%; investigational agents, OR 10% & CCR 0%. SURVIVAL. UNT pts had a favorable survival substantially better than that reported in previous studies (median not reached, 2 yr survival 81%), whereas RR pts had a median survival of only 14 months (p<0.0001). Among RR pts, those with a normal performance status (n=35) had a favorable 2 year survival of 78%, with no deaths between 12 and 46 months. Conclusions: The outcome of 17p- CLL is not necessarily dismal. Half of early stage pts will not require therapy at a follow-up of up to 4 years. The 17p- clone may be lost spontaneously or be eliminated by effective therapy. Rituximab containing regimens are highly effective particularly in the frontline setting. No significant financial relationships to disclose.

Chronic lymphocytic leukemia in Turkey: experience of a single center in Istanbul.

In this study, the clinical characteristics, survival, and prognostic factors of 200 patients diagnosed as having chronic lymphocytic leukemia (CLL) were analyzed. The medical charts of 200 CLL patients registered to our center between 1984 and 2000 were retrospectively evaluated. Of all patients, 129 were men and 71 were women (male/female ratio, 1.82). The median age at the time of initial diagnosis was 63 years (range, 38-90 years). Sixty patients were classified as Binet's Stage A, 49 as Stage B, and 91 as Stage C. Sixty-two cases were diagnosed during routine laboratory examinations when they were asymptomatic. Forty-three patients were lost to follow-up, and 157 patients have been followed regularly until the end of the study period. Hemolytic anemia developed in nine (5.7%) patients, second primary cancer in six (3.8%), and Richter's syndrome in two (1.2%). Forty-eight percent of CLL patients were treated immediately after initial diagnosis. The overall response (complete or partial) to first-line and second-line therapies was 61.6% and 54.4%, respectively. The median time of follow-up for patients followed up regularly was 47 months (range, 1-195 months). Sixty-three patients died during the follow-up: the deaths of 39 (62%) of these were attributable to CLL-related causes. The median survival time was 48 months. The 5-year survival rate was 36.5% and the 10-year survival rate was 8%. Stage according to Rai's classification, lymphocyte count, and age showed a significant prognostic effect on survival by univariate analysis. On multivariate analysis, advanced age and lymphocyte count were independent prognostic parameters. In our study, more asymptomatic CLL patients have been diagnosed in recent years. The survival, especially of our early-stage patients, was shorter than that in other CLL series of Western origin. Rai's staging system was seen to determine prognosis better than Binet's staging system.

Changes in membrane markers and chromosome patterns in chronic T-cell leukemia

A patient with asymptomatic chronic lymphocytic leukemia (CLL) and only moderate lymphocytosis has been followed for 2.5 years. Originally, surface membrane markers and response to T-cell mitogens (phytohemagglutinin, concanavalin A, A23187) indicated a T-cell neoplasm. Over time, these T-cell properties were gradually lost [e.g., cells forming sheep erythrocyte (E) rosettes decreased from 77 to 16%]. Concomitantly, an expanding chromosomally abnormal clone, including a 14q + marker, became demonstrable in peripheral blood cultures stimulated by T-cell mitogens. There has been no change in clinical course nor in the morphology of the circulating lymphocytes. The results indicate that membrane markers and chromosome patterns can change during the course of CLL, presumably reflecting the emergence of new subpopulations during clonal evolution of the disease. In this instance, clinical progression has not occurred simultaneously, and additional data are needed to determine the prognostic value of such longitudinal studies.

Large Doses of Prednisone and Prednisolone in the Treatment of Malignant Lymphoproliferative Disorders

Article1 November 1962Large Doses of Prednisone and Prednisolone in the Treatment of Malignant Lymphoproliferative DisordersROBERT A. KYLE, M.D., CLIFTON E. MCPARLAND, M.D., WILLIAM DAMESHEK, M.D., F.A.C.P.ROBERT A. KYLE, M.D.Search for more papers by this author, CLIFTON E. MCPARLAND, M.D.Search for more papers by this author, WILLIAM DAMESHEK, M.D., F.A.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-57-5-717 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTreatment of the generalized chronic malignant lymphoproliferative disorders*is not standardized at all. In asymptomatic chronic lymphocytic leukemia, the best treatment is often no treatment. In the "aggressive" cases of chronic lymphocytic leukemia (1) and in generalized or disseminated lymphosarcomatosis, one of several therapeutic programs may be preferred. These include treatment with roentgen rays, nitrogen mustard, or one of the other alkylating agents [triethylene melamine (TEM), chlorambucil (Leukeran), or cyclophosphamide (Cytoxan)]; and corticosteroids. Each form of therapy has its adherents, and each may be said to have a special value in some phases of the patient's illness. In the last...