Diagnosis Of Chronic Lymphocytic Leukemia Research Articles

Evaluation of the Effects of Prognostic Factors on Clinical Findings and Survival in Patients With a Diagnosis of Chronic Lymphocytic Leukemia

Evaluation of the Effects of Prognostic Factors on Clinical Findings and Survival in Patients With a Diagnosis of Chronic Lymphocytic Leukemia

Independent diagnostic utility of CD20, CD200, CD43 and CD45 in chronic lymphocytic leukaemia

Immunophenotyping plays a major role and is essential for establishing the diagnosis of chronic lymphocytic leukemia (CLL). Though CLL has a characteristic phenotype, diagnosis may be challenging due to immunophenotypic overlap with other B cell non-Hodgkin’s lymphomas (B-NHL). Markers like CD200, CD43, CD20 and CD45 were found valuable in CLL and we investigated their diagnostic efficiency and accuracy in 174 patients with leukemic B-NHL. On the integration of four markers by a scoring system, 96% (49/51) of CLL cases showed a score of 3 or 4 and 90% (36/40) of non-CLL cases had a score of 0 or 1. This scoring system for CLL diagnosis showed a sensitivity of 98.2% and 96% in the analytical cohort and validation cohort respectively, which was significantly higher than the classical Matutes score. Hence we strongly suggest considering the expression of CD200, CD20, CD43 and CD45 in the diagnosis of B-NHL cases.

Flowcytometry Aiding Morphological Diagnosis of Mature B-Cell Neoplasm in Patients with Lymphocytosis

Background: Mature B-cell neoplasms (MBCNs) are a category of disorders with a broad range of clinical manifestations, pathologic features, and outcomes that share common characteristics. They originate from the B-cell lineage, are clonal, and have the immunophenotypic and genetic features of mature B-cells. Flow cytometry (FC) is a widely used method for diagnosing suspected lymphoproliferative disorders in patients with lymphocytosis, lymphadenopathy, and other lymphoproliferative disorders. Aim: To evaluate the role of FC in confirming the provisional morphologic diagnosis in patients with MBCNs. Materials and Methods: This is a retrospective; descriptive study conducted on 193 adult patients newly diagnosed with MBCNs; immunophenotypic findings of the patients were reviewed. The B lymphocytes were identified according to their Side-Scattered/CD19 distribution. Results: Chronic lymphocytic leukemia (CLL) was the most common subtype (127, 65.9%). Splenomegaly was noted more frequently in hairy cell leukemia variant cases (85.7%) and hairy cell leukemia cases (75%). The anemia at presentation was the least frequent in CLL (20%). The CD5+/CD23+ phenotype of CLL was seen in 114 cases (90%); negativity for FMC7 showed high sensitivity (93.7%) and sufficient specificity (60%) in the diagnosis of CLL. Conclusions: It is difficult to diagnose B-chronic lymphoproliferative disorders solely based on morphologic findings. Consequently, FC findings combined with clinical, hematologic, and morphologic features can confidently result in a precise diagnosis.

TIME-DEPENDENT, LIFE-SAVING SUPPORTIVE TREATMENT IN AN UNORDINARY PULMONARY LEUKOSTASIS PRESENTATION: A CASE REPORT

TOPIC: Pulmonary Manifestations of Systemic Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Pulmonary leukostasis (PL) is a medical emergency defined by an extremely high white blood cell count (WBC) with pulmonary symptoms with or without imaging findings. This condition is seen more frequently in acute myeloid leukemia or chronic myeloid leukemia during a blast crisis and confers up to 30% mortality. Symptoms usually do not occur unless WBC exceeds 400x10ˆ3 / µL in patients with chronic lymphocytic leukemia (CLL). Here we present an atypical presentation of this dreaded disease. CASE PRESENTATION: An 80-year-old man with a history of atrial fibrillation, benign prostatic hyperplasia, diabetes mellitus, and a recent diagnosis of chronic lymphocytic leukemia came to the emergency room with tachypnea, hypoxia, headache, slurred speech, drowsiness, and confusion. Days before his arrival, he began with bradyphrenia, subjective fever, and dry cough. Vital signs with tachypnea and peripheral oxygen saturation of 90%. Routine laboratories stood out for 95.2 x10ˆ3 / µL white blood cells, with 65% immature blood cells, 17% lymphocytes, 10% neutrophils, and arterial blood gas with metabolic alkalosis and hypoxemia. Supportive therapy began with respiratory therapies every four hours, aggressive intravenous hydration, and empirical antibiotics. Chest radiography and chest computed tomography failed to show effusions, infiltrates, or consolidations. Brain studies negative for intracranial pathology. Debulking and leukoreduction therapies were discussed with the patient who decided to continue with supportive therapy, even with the risk of tumor lysis. After observation and aggressive hydration, there was a significant clinical improvement that correlated with the decrease in WBC from 95.2x10ˆ3 / µL to 69.9x10ˆ3 / µL. Noteworthy, cultures and respiratory panel were negatives. The following days the antibiotics were suspended and the patient was discharged with scheduled chemotherapy. DISCUSSION: Leukostasis is an emergency condition that, if overlooked or misdiagnosed, could be fatal if left untreated. In case of clinical suspicion, expeditious treatment is indicated since the mortality rate is approximately 20 to 40 percent regardless of the leukocytosis. CONCLUSIONS: Although it is less common in CLL and almost unthinkable with WBC less than 100x10ˆ3 / µL; L This case highlights the important role of high clinical suspicion of PL even if not all medical criteria are met and its response to supportive and symptomatic therapy when implemented in a rapid timely manner. REFERENCE #1: Kacar, D., Yarali, N., Candir, M. O., Kara, A., Ozbek, N., & Tunc, B. (2017). Pulmonary Leukostasis. Journal of Pediatric Hematology/Oncology, 39(2), 156–158. doi:10.1097/mph.0000000000000731 REFERENCE #2: Soares, F. A., Landell, G. A. M., & Cardoso, M. C. de M. (1992). Pulmonary leukostasis without hyperleukocytosis: A clinicopathologic study of 16 cases. American Journal of Hematology, 40(1), 28–32. doi:10.1002/ajh.2830400106 REFERENCE #3: Baer, M. R., Stein, R. S., & Dessypris, E. N. (1985). Chronic lymphocytic leukemia with hyperleukocytosis the hyperviscosity syndrome. Cancer, 56(12), 2865–2869. doi:10.1002/1097-0142(19851215)56:12<2865::aid-cncr2820561225>3.0.co;2-6 DISCLOSURES: No relevant relationships by Ian Da Silva Lugo, source=Web Response No relevant relationships by Arelis Febles, source=Web Response No relevant relationships by Juan Feliciano-FIgueroa, source=Web Response No relevant relationships by Heydee Fournier, source=Web Response No relevant relationships by Joel Gonzalez Chaple, source=Web Response No relevant relationships by Juan Santiago, source=Web Response

AORTOILIAC THROMBOSIS AND LYMPHOCYTOSIS IN A PATIENT WITH COVID-19

TOPIC: Critical Care TYPE: Fellow Case Reports INTRODUCTION: Venous thromboembolism (VTE) and arterial thrombosis (AT) are known complications associated with critically ill COVID-19 patients. We report a case of a patient that developed an acute aortoiliac thrombosis and acute limb ischemia despite high-dose VTE prophylaxis and was subsequently found to have chronic lymphocytic leukemia (CLL). CASE PRESENTATION: A 62-year-old male with coronary artery disease and diabetes was admitted to the intensive care unit for acute hypoxemic respiratory failure from COVID-19 pneumonia. He was treated with Remdesivir, dexamethasone 6mg daily, and enoxaparin 30mg twice daily. On hospital day 5, he developed acute left lower extremity pain with sensory and motor loss and bilateral lower extremities became cold and pale. He had no palpable femoral or popliteal pulses and posterior tibial and dorsalis pedis pulses were not detected by doppler. A CTA demonstrated an acute, nearly occlusive thrombus at the level of the distal infrarenal aorta with extension to bilateral iliac and femoral arteries. The patient was taken emergently to the operating room and underwent percutaneous thrombectomy and left lower extremity fasciotomy. On further review, he was noted to have significant lymphocytosis (83% on admission), an unexpected finding for a patient with COVID-19. As a result, peripheral flow cytometry was performed and demonstrated CD5 positive B-cell leukemia. The patient eventually discharged to acute rehab after a 42-day hospitalization. DISCUSSION: Since the start of the pandemic, the thrombotic complications of COVID-19 have been a major research focus given the high incidence and associated increased risk of mortality. Most of the research has centered around VTE as the incidence among ICU patients with COVID-19 is estimated at 20-30%. The rate of AT is much less with an overall incidence between 2-4% and only 0.4% associated with acute limb ischemia. Our patient was at higher risk for thrombotic complications given his underlying but undiagnosed CLL. His lymphocytosis was striking, particularly because lymphopenia is the usual finding in patients with COVID-19, and further work up revealed the CLL diagnosis. CONCLUSIONS: Thrombotic complications are common and carry a higher risk of mortality in patients with COVID-19. While the rate of AT is much less compared with VTE, critical care practitioners must remain vigilant, particularly when patients are receiving mechanical ventilation and unable to report symptoms, and be mindful of other conditions, potentially undiagnosed, that may further predispose to thrombosis. REFERENCE #1: Jimenez D, Garcia-Sanchez A, Rali P, Muriel A, Bikdeli B, Ruiz-Artacho P, Le Mao R, Rodriguez C, Hunt BJ, Monreal M. Incidence of VTE and Bleeding Among Hospitalized Patients With Coronavirus Disease 2019: A Systematic Review and Meta-analysis. Chest. 2021 Mar;159(3):1182-1196. REFERENCE #2: Malas MB, Naazie IN, Elsayed N, Mathlouthi A, Marmor R, Clary B. Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: A systematic review and meta-analysis. EClinicalMedicine. 2020 Dec;29:100639. REFERENCE #3: Tan BK, Mainbourg S, Friggeri A, Bertoletti L, Douplat M, Dargaud Y, Grange C, Lobbes H, Provencher S, Lega JC. Arterial and venous thromboembolism in COVID-19: a study-level meta-analysis. Thorax. 2021 Feb 23:thoraxjnl-2020-215383. DISCLOSURES: No relevant relationships by Amanda Jobe, source=Web Response No relevant relationships by Mohamed Ramez Mourad, source=Web Response

CLL-153: Evaluation of Second Primary Cancer Risk Among Chronic Lymphocytic Leukemia Patients: Multicenter Study

Context: Patients with chronic lymphocytic leukemia (CLL) have an increased risk of developing second primary cancers (SPC). Although cytogenetic disorders and some risk factors (such as ZAP 70, IGHC mutation) are held responsible, there is no definitive explanation for the increased cancer risk. Objective: Determining the frequency of SPC in CLL patients and determining the relationship between these cancers and the treatment status of CLL, cytogenetic factors, and other risk factors were the study aims. Design: The study was designed as a multicenter and retrospective study. The sample comprised 553 subjects with CLL diagnosis. Data collection commenced in August 2016 and was completed in May 2021. Results: Fifty-one of 553 patients followed for CLL had a history of SPC. The SPC development rate was 9.2%. The duration of CLL disease was 2.7 years, on average, at the time of SPC detection. Epithelial tumors were mostly observed. According to the incidence, the tumor types were skin, lymphoma, renal, breast, lung, gastrointestinal system, thyroid, malignant melanoma, prostate, Kaposi sarcoma, neuroendocrine tumor, ovarian, larynx, and salivary gland. The 13q deletion was the most common genetic abnormality in those who developed SPC, and the frequency of the 13q deletion was found to be increased significantly in those with malignancy compared to those without malignancy. Conclusion: In CLL patients with SPC, older age at diagnosis, 13q deletion, CD38 positivity, and treatment with fludarabine and monoclonal antibodies were found to be risk factors. We determined that SPC frequency increased independently from hemogram values, β2 microglobulin levels at diagnosis, the number of treatment lines, and genetic mutations other than 13q in CLL patients. In addition, the mortality rate was higher in CLL patients with SPC, and they were prone to be in advanced stages at the time of diagnosis. Patients with chronic lymphocytic leukemia (CLL) have an increased risk of developing second primary cancers (SPC). Although cytogenetic disorders and some risk factors (such as ZAP 70, IGHC mutation) are held responsible, there is no definitive explanation for the increased cancer risk. Determining the frequency of SPC in CLL patients and determining the relationship between these cancers and the treatment status of CLL, cytogenetic factors, and other risk factors were the study aims. The study was designed as a multicenter and retrospective study. The sample comprised 553 subjects with CLL diagnosis. Data collection commenced in August 2016 and was completed in May 2021. Fifty-one of 553 patients followed for CLL had a history of SPC. The SPC development rate was 9.2%. The duration of CLL disease was 2.7 years, on average, at the time of SPC detection. Epithelial tumors were mostly observed. According to the incidence, the tumor types were skin, lymphoma, renal, breast, lung, gastrointestinal system, thyroid, malignant melanoma, prostate, Kaposi sarcoma, neuroendocrine tumor, ovarian, larynx, and salivary gland. The 13q deletion was the most common genetic abnormality in those who developed SPC, and the frequency of the 13q deletion was found to be increased significantly in those with malignancy compared to those without malignancy. In CLL patients with SPC, older age at diagnosis, 13q deletion, CD38 positivity, and treatment with fludarabine and monoclonal antibodies were found to be risk factors. We determined that SPC frequency increased independently from hemogram values, β2 microglobulin levels at diagnosis, the number of treatment lines, and genetic mutations other than 13q in CLL patients. In addition, the mortality rate was higher in CLL patients with SPC, and they were prone to be in advanced stages at the time of diagnosis.

CLL-376: Clinical Characteristics and Outcomes of Patients with Chronic Lymphocytic Leukemia (CLL), 80 Years of Age or Older

Context: Nearly 20% patients are ≥80 years of age at CLL diagnosis. Increased comorbidities often accompany advanced age. However, clinical trials enroll a disproportionally low number of people this age, providing limited evidence for guidance. Objective: To determine clinical characteristics and outcomes of patients ≥80 years of age at the time of CLL diagnosis. Design: Retrospective. Setting: Academic. Patients or Other Participants: Between 1/1995–3/2020, we identified previously untreated CLL patients from the Mayo Clinic CLL Database ≥80 years of age at the time of CLL diagnosis and seen within 3 years of diagnosis. Main Outcomes Measures: Baseline characteristics, treatments, and time-to-first-treatment (TFT) were analyzed for all patients. Overall survival (OS) was measured from diagnosis date in all patients and separately from treatment date for treated patients. Time-to-next-treatment (TTNT) was measured in treated patients from the first treatment date to the date of second treatment or last known treatment. TFT and TTNT were analyzed accounting for competing risk of death. Cox multivariable regression models were used to determine which factors were associated with OS and TTNT. Results: Among 213 patients identified, the median age was 83 years (range 80–97). The median number of medical comorbidities among all patients was 4 (range 0–8). Fifty-six patients received treatment; median TFT 6.7 years. Treatment approaches included monoclonal antibody alone (n=17), chemotherapy alone (n=17), chemoimmunotherapy (n=14), novel agents (n=3), and multi-agent Richter’s transformation regimens (n=5). Twenty-two of 56 treated patients received second-line therapy (median TTNT 2.8 years). Median OS among all 213 patients was 4.6 years. Standardized mortality ratio was 1.2 (p=0.008), excluding patients with Richter’s transformation. In univariable analyses, receipt of therapy (HR 3.92, 95%CI 2.11–7.28; p Conclusions: Survival was similar across the 25-year span of this study; however, patients treated with novel agents were underrepresented and warrant additional evaluation. The 20% higher risk of death compared to an age- and sex-matched population emphasize the need for ongoing efforts to improve clinical outcomes for CLL patients in this growing demographic.

Impact of Chronic Lymphocytic Leukemia on Outcomes and Readmissions After Cardiac Operations

BackgroundOutcomes of cardiac operations in patients with chronic lymphocytic leukemia (CLL) have been examined in limited series. The present study aimed to assess the impact of CLL on clinical outcomes and resource utilization after cardiac operations in a nationally representative cohort. MethodsAll adult patients undergoing elective coronary artery bypass grafting, valve repair, or valve replacement were identified utilizing the 2010 to 2017 Nationwide Readmissions Database. Patients were stratified by history of CLL. Incidence of in-hospital mortality, perioperative complications, blood transfusions, and readmission within 90 days were examined. We subsequently performed 3:1 nearest neighbor matching between CLL and non-CLL patients for all primary and secondary outcomes of interest. ResultsOf an estimated 1,250,882 patients undergoing cardiac operations, 0.23% had a diagnosis of CLL. Among 11,237 propensity matched patients, those with CLL had similar rates of in-hospital mortality (3.8% vs 2.6%; P = .08) and perioperative complications (33.4% vs 33.6%; P = .92) compared with their non-CLL counterparts. Although the incidence of infection was comparable (8.5% vs 9.4%; P = .38), CLL patients did require blood transfusions more frequently (33.7% vs 28.4%; P = .003) than others. Furthermore, CLL patients were more likely to be readmitted with respiratory etiologies contributing significantly to rehospitalization. ConclusionsPatients with CLL generally have similar outcomes after cardiac operations but may more commonly require blood transfusion. Blood-conserving interventions may be considered in this at-risk population to improve outcomes. Furthermore, interventions to mitigate readmission deserve further exploration.

Larynx Angioedema as a Signal in Chronic Lymphocytic Leukemia: A Case-based Guide for Acquired Angioedema in the Setting of Lymphoproliferative Disorders

ABSTRACT Patients with angioedema can present to the internal medicine, emergency medicine, dermatology, or ear nose throat clinics. Physicians may need to assess the patients whose angioedema is unresponsive to antihistamines systematically in collaboration with other subspecialties including hematology, rheumatology, allergy, and immunology. We aimed to provide a concise review of the diagnosis and multi-disciplinary management of acquired angioedema through a case presentation. A 61-year-old woman presented with recurrent angioedema of 4 episodes within one year. She was evaluated by various disciplines such as dermatology and emergency medicine. Antihistamines and steroids were not effective. The complete blood count (CBC) results indicated lymphocytosis (lymphocyte count=9100 k/μL) and further evaluation of the lymphocytosis with flow cytometry immunophenotyping confirmed a diagnosis of chronic lymphocytic leukemia. Since the acquired angioedema diagnosis was confirmed with low C4, C1q, and C1 esterase inhibitor levels, Rituximab 375 mg/m2 was administered once a week for 4 weeks. The frequency of attacks decreased after rituximab therapy and none of them were life-threatening. In conclusion, when the effective treatment is initiated for the primary diagnosis in acquired angioedema, the numerous emergency department visits, hospitalizations, and the mortality due to life-threatening angioedema episodes can be avoided. Keywords: Angioedema, larynx angioedema, emergency, chronic lymphocytic leukemia, life-threatening angioedema

Bioinformatics Analysis of Merkel Cell Carcinoma to identify critical genes and their validation

Merkel Cell Carcinoma (MCC) is a destructive form of neuroendocrine carcinoma that represents the 2nd highest cause of skin cancer related deaths despite being a relatively rare form of cancer. Different risk factors have been associated with MCC such as advancement age, immunosuppression, and ultraviolet light exposure, polyomavirus infection and a current, concurrent or previous diagnosis of Chronic Lymphocytic Leukaemia (CLL). However, the exact mechanism that leads to MCC and its inherent biology is yet to be fully researched and explored. The current treatments for MCC are a combination of surgery and radiation or chemo-radiation. So far, only two drugs have been approved by FDA for the treatment of MCC, with both drugs being immune checkpoint inhibitors. However, the drug approval from FDA was accelerated based on promising results from a relatively small number of patients, which means that the more research and trials are undergoing currently considering the fact that a very small cohort was used for clinical trials. Presently there are no biomarkers indicative of MCC and additional research is essential. With the advent of bioinformatics and microarray technology, in silico approaches pertaining to ‘omics’ data analysis, shall allow identification of hub genes and miRNA to broaden our understanding of MCC biology and their clinical utility.

Statins in mature B-cell lymphomas and leukaemias.

Statins in mature B-cell lymphomas and leukaemias.

Cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia: a systematic review of the literature.

The continuous improvement of life expectancy of patients with chronic lymphocytic leukemia (CLL) has resulted in increased risk of second primary malignancy that potentially may affect survival and quality of life of CLL patients. We performed a systematic review to assess the risk and the clinical‐pathological features and prognosis of cutaneous squamous cell carcinoma (cSCC) in patients with CLL. We searched PubMed, Embase, and Cochrane Central Register of Control Trials databases for articles published from database inception to December 31, 2019. English‐language studies reporting original data on patients with a specific diagnosis of CLL and cSCC were included. Data were extracted using a standardized extraction form, and any discordance was resolved by consensus. Descriptive data were generated by pooling patients from eligible studies. Of the 4588 non‐duplicate records identified, 55 articles met our inclusion criteria. These studies reported that CLL patients have a 3.2% prevalence of cSCC, with an 11.5% cSCC‐related lethality and an overall risk of metastasis of 5.7% (7.3% for regional lymph node involvement and 3.8% for distant metastasis). The quality of evidence was limited by the high heterogeneity in the design, populations, and objectives of the included studies. This systematic review suggests that cSCC in CLL patients tends to behave less aggressively compared with the solid organ transplant recipients but has a higher morbidity and mortality than in the general population. Future prospective studies are needed to increase the quality of evidence and to determine the best treatment modalities and screening intervals for these patients.

Clinical characteristics of chronic lymphocytic leukemia in young versus old age patients in Kurdistan region- Iraq

Background: Chronic lymphocytic leukemia is the common adulthood leukemic type, although the incidence rate in the Kurdistan region is low. It is well known that chronic lymphocytic leukemia is prevalent among the elderly age group, however frequent cases of chronic lymphocytic leukemia are newly diagnosed at a younger age. Aim of the study: To analyze the difference in disease presentation, progression, and outcome between young and old age group patients with chronic lymphocytic leukemia in the Kurdistan region/Iraq. Patients &amp; Methods: A retrospective cross-sectional review study carried out in three oncology centers in the Kurdistan region (Nanakaly Hospital in Erbil city, Hiwa center in Sulaimani city, and Azadi center in Duhok city) for ten years through the period from 1st of January, 2010 to 31st of December, 2019 on a convenient sample of 152 patients with chronic lymphocytic leukemia. Diagnosis of chronic lymphocytic leukemia was done by the Oncologists in Kurdistan tumor centers according to the International Workshop on Chronic Lymphocytic Leukemia. The age of patients at diagnosis was categorized into two groups and ranged from 25 years to 94 years. The age cutoff value in the current study was (55 years) depending on previous kinds of literature. Results: The mean age at diagnosis of patients was (63 years); 28% of them were diagnosed at age of ≤50 years and 72% of them were diagnosed at age of more than 55 years. Older age patients were significantly presented with weight loss, while younger age patients were significantly presented with neck lumps. There was a highly significant association between the advanced ECOG performance scale and older age patients at diagnosis. A significant association was observed between the death outcome of chronic lymphocytic leukemia and older age patients at diagnosis. The mean survival duration of younger age patients at diagnosis was significantly longer than the mean survival duration of older age patients at diagnosis. Conclusions: clinical presentation, physical status, death rates, and survival of patients with chronic lymphocytic leukemia in Kurdistan region-Iraq are different between young and older age patients. Keywords: Chronic Lymphocytic Leukemia, age, death, Survival.

Survival trends in chronic lymphocytic leukemia across treatment eras: US SEER database analysis (1985-2017).

In this population-based study, we used the SEER database (1985-2015) to examine survival outcomes in chronic lymphocytic leukemia (CLL) patients followed up to the era of advanced treatments including targeted therapies. Data were extracted for patients 15years or older with a primary diagnosis of CLL. A period analysis was performed to estimate 5- and 10-year relative survival rates for patients diagnosed during different calendar periods from 1985 to 2015. A mixture cure model was used to examine long-term survivors' proportions among patients diagnosed in 1985-2015 and for two cohorts diagnosed in 2000-2003, followed up to 2012 and 2004-2007, and followed up to 2015. Cox proportional hazard modeling was used for the two cohorts to estimate hazard ratios (HRs) of death adjusted for gender and age. The 5-year and 10-year age-adjusted relative survival rate ranged between 73.7 and 89.4% and from 51.6% to "not reached," respectively, for calendar periods of 1985-1989 to 2010-2014. The long-term survivor proportions varied by age and gender from 0 to 59%. The HRs (95%CI) for the 2004-2007 cohort in comparison to the 2000-2003 cohort were 0.58 (0.43-0.78), 0.58 (0.48-0.70), 0.57 (0.49-0.0.67), 0.68 (0.54-0.85), and 0.83 (0.68-1.02) for the age categories of 45-54, 55-64, 65-74, 75-84, and ≥ 85years, respectively. Overall, relative survival improved significantly for CLL patients diagnosed between 1985 and 2015. These improvements were markedly better following the introduction of targeted therapies.

Evaluation and associated risk factors for neutropenia with venetoclax and obinutuzumab in the treatment of chronic lymphocytic leukemia.

BackgroundThe time‐limited combination of venetoclax and obinutuzumab (VenG) was established by the German CLL Study Group in the CLL14 trial for the upfront management of newly diagnosed chronic lymphocytic leukemia (CLL), showing a superior progression free survival benefit. The incidence of grade 3–4 neutropenia was reported in the range of 52.8%–57.7%. However, patients who develop neutropenia with this combination have yet to be formally characterized in the literature as it has impact on the clinical practice setting.AimTo determine the incidence of grade 3 and 4 neutropenia and identify risk factors for neutropenia among CLL patients treated with the VenG regimen.MethodsWe conducted a retrospective, single‐center study of all adult patients with a diagnosis of CLL treated with VenG at the University of Colorado Hospital. Demographic information, laboratory data, clinical data, and medication prescriptions were collected from the patients' electronic medical record.ResultsA total of 14 patients (73%) developed neutropenia during the course of therapy. The mean time to neutropenia from the start of treatment was 42 days (range 1–131). Our cohort harbored more high risk disease features and more comorbidities (CIRS score of 12). Four patients (28.6%) in the neutropenic group developed infectious complications during therapy and 6 (31%) patients were unable to be dose escalated to the final FDA approved dose of 400 mg.ConclusionOur study cohort had higher incidence of grade 3 and 4 neutropenia occurring in 73% of patients. This could be attributed to a higher rate of comorbidities, high risk features, concomitant interacting medications, and prior chemotherapy. Further studies are warranted to determine if growth factor support is efficacious to achieve dose escalation with this therapy.

The potential differential diagnosis value and clinical significance of CD35 expression in B-chronic lymphoproliferative disorders.

BackgroundFlow cytometry for immunophenotyping is the main method for diagnosing chronic lymphocytic leukemia (CLL). Differential diagnosis between CLL and other B-chronic lymphoproliferative disorders (B-CLPDs) is sometimes difficult. This study aimed to investigate whether cluster of differentiation 35 (CD35) could be a useful marker for the differential diagnosis of CLL and other B-CLPDs.MethodsThe CD35 expression on lymphoma cells from 516 B-CLPD patients (347 CLL, 169 other B-CLPDs) was investigated through flow cytometry analysis. Serum C3 and C4 levels in B-CLPD patients were also evaluated.ResultsThe results showed that the expression percentage and mean fluorescence intensity of CD35 were reduced in CLL cases compared with other B-CLPD patients. Furthermore, CD35 <17% produced a sensitivity of 81.8% and a specificity of 88.4% for supporting the diagnosis of CLL. Additionally, the addition of CD35 to Matutes score improved the score’s discriminative power. The sensitivity of the Matutes score was improved from 81.3% to 88.5%, and the accuracy was improved from 96.6% to 97.6%. Finally, 15.0% and 16.4% of CLL patients had defective serum C3 and C4 levels at diagnosis, respectively.ConclusionsEvaluating CD35 expression could have potential differential diagnostic value in distinguishing CLL from other B-CLPDs, especially between CLL and mantle cell lymphoma (MCL).

Factors Associated with Non-Melanoma Skin Cancer (NMSC) Among Chronic Lymphocytic Leukemia (CLL) Patients

Background: The incidence of NMSC in patients with CLL is significantly higher compared to age- and sex- matched controls. Herein, we evaluate factors associated with risk of NMSC post-CLL diagnosis, including CLL clinical and prognostic characteristics, history of UV radiation exposure, severe sunburn, and combined genetic score of single nucleotide polymorphisms (SNPs) associated with NMSC.Methods: CLL patients newly diagnosed from 2002-2015 were enrolled and systematically followed by the Mayo Clinic/University of Iowa Lymphoma SPORE. Clinical and prognostic CLL data were obtained from the Mayo Clinic CLL database. NMSCs were abstracted both from medical records and from patient self-report. Self-reported history of the extent of mid-day sun exposure (h/week) at various ages (<13, 13-21, 22-40, >40 yrs) and severe sunburn were obtained from a risk factor questionnaire. The CLL International Prognostic Index (CLL-IPI) was computed as established using a weighted average of five independent CLL prognostic factors (IGHV mutational status, serum b2-microglobulin, Rai stage, age at CLL diagnosis and FISH 17p deletion/ TP53 status). CLL treatment was classified as positive if a person received T-cell immunosuppressive treatments that are purine analogue and/or alemtuzumab based treatments. All other therapies were combined into an “other category”. We computed a polygenetic risk score (PRS), a weighted average of the number of risk alleles across 13 SNPs that are known to be associated with NMSC, with the weights being the log of the odds ratio reported for each SNP. To evaluate associations with risk of NMSC post-CLL diagnosis we used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). CLL treatment was considered a time-dependent covariate in the analysis.Results: Among 1269 CLL patients, the median age at diagnosis was 63 years (range 24-91), 68% were male, and 6% had Rai stage III-IV at diagnosis. Based on the CLL-IPI, 44% were low risk, 34% intermediate risk, and 22% high/very-high risk. 9% of the CLL cases had prior history of NMSC and 44% reported history of severe sun burn. At a median follow-up of 7 years from CLL diagnosis, 196 patients had ≥1 NMSCs post-CLL diagnosis. Among these patients, 45 also had NMSC before CLL diagnosis. The most frequent NMSC was squamous cell carcinoma (63%), followed by basal cell (55%), and Merkel cell (1%). 264 patients received T-cell immunosuppressive treatments prior to NMSC diagnosis or prior to last follow up. Significant associations of clinical and prognostic characteristics with risk of NMSC post-CLL diagnosis were observed for age (HR=1.42 per 10 year increase, CI=1.24-1.62), male sex (HR=1.43, CI=1.04-1.97), prior history of NMSC (HR=3.85, CI=2.75-5.39), and CLL-IPI (HR=1.36, CI=1.13-1.64, adjusted for sex and prior NMSC). Mid-day sun exposures for each of the age groups considered showed no evidence of association with risk of NMSC post-CLL diagnosis; however, history of severe sunburn was significantly associated (HR=1.58, CI=1.06-2.36, adjusted for sex, CLL-IPI and prior NMSC). We observed an association between T-cell immunosuppressive treatments with risk of NMSC post-CLL diagnosis (HR=1.65, CI=1.14-2.40, adjusted for age, sex and prior NMSC). PRS was also associated with the risk of NMSC post-CLL diagnosis (HR=1.82, CI=1.21-2.72, adjusted for sex, CLL-IPI and prior NMSC).Conclusion: Screening for NMSC is important in CLL patients, and our data suggest that it is particularly important among patients with aggressive CLL according to CLL-IPI score, those receiving T-cell immunosuppressive treatments that are purine analogue and/or alemtuzumab based treatments, those who have a prior history of NMSC, or history of severe sunburn. PRS was also a significant factor in the risk of NMSC among CLL patients. Future studies should develop prediction models that include these factors. [Display omitted] DisclosuresKay:Tolero Corporation: Research Funding; Gilead: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding. Shanafelt:Genentech, Celgene, Pharamacyclics, Jansen, GlaxoSmithKline, AbbVie, Hospira, and Cephalon: Research Funding. Cerhan:Janssen: Other: Multiple Myeloma Registry Steering ; Janssen: Other: Scientific Advisory Board (REMICADELYM4001).

Clinical Benefits of Achieving Deep Remission to Second-Line Therapy in Patients with Relapse/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) - a Real-World Study

▪Introduction: Deep remission to first-line chemoimmunotherapy for chronic lymphocytic leukemia (CLL), especially undetectable minimal residual disease (MRD-), was associated with longer progression-free (PFS) and overall survival (OS). (Kovacs 2016, Kwork 2016) Patients with relapsed/refractory (R/R) CLL represent a more difficult and complex population to treat. The benefits of achieving deep response to second-line therapy in R/R CLL have not been reported. This study aimed to describe patient characteristics, PFS, and OS in patients with R/R CLL who achieved clinical complete remission (CCR) from second-line therapy compared to patients who did not achieve CCR in a real-world setting.Methods: Patient-level data was abstracted from medical charts by 85 oncologists/hematologists in the United States between April and June 2017. Data were collected for adult patients with R/R CLL who initiated a second-line pharmacological therapy between January 1, 2010 and Augusts 31, 2015. Data on disease progression, mortality, and best response to second-line therapy was reported by the treating oncologists/hematologist; iwCLL 2008 criteria were provided to guide assessment of treatment response. Patients were categorized into two cohorts based on best response to second-line therapy: patients who achieved CCR (CCR cohort) and patients who did not achieve CCR (non-CCR cohort). The non-CCR cohort included patients with partial remission (PR), stable disease (SD) and progressive disease (PD). Sample size for each response cohort (i.e., CCR, PR, SD, and PD) was determined a priori based on distribution of responses seen in clinical trials. PFS and OS were compared between the CCR and non-CCR cohorts using Cox proportional analyses. Exploratory analyses compared outcomes between patients with and without MRD- among those who achieved a CCR or PR and had an MRD assessment. Multivariate models adjusted for potential differences in demographic and clinical characteristics between CCR and non-CCR cohorts (i.e., gender, age at R/R CLL diagnosis, del [17p] status, Rai staging and ECOG status at second-line therapy initiation) and between cohorts with and without MRD- (i.e., gender, age at R/R CLL diagnosis, chronic renal failure, and ECOG status).Results: Data was collected on 306 patients with R/R CLL - 153 patients with CCR and 153 patients who did not achieve CCR (102 patients with PR, 40 with SD, and 11 with PD). Most common regimens received in second-line therapy were novel targeted therapies (CCR cohort: 42.5%; non-CCR cohort: 52.3%) and combination of rituximab and bendamustine (CCR cohort: 27.5%; non-CCR cohort: 19.6%). Most patients were male (70.6%). Patients in the non-CCR cohort were older (median of 66 vs. 63 years old) than patients in the CCR cohort; a higher proportion of patients in the non-CCR cohort had a Rai stage of III-IV (62.1% vs. 50.3%), an ECOG status of 2+ (33.9% vs. 13.1%), and del (17p) (26.1% vs. 13.1%) at second-line therapy initiation compared to the CCR cohort. The median observation period after second-line therapy initiation was 26.8 months in the CCR cohort and 23.1 months in the non-CCR cohort. Compared to patients in the CCR cohort, patients in the non-CCR cohort had an over 2-fold higher hazard of progression/death (adjusted hazard ratio [HR]=2.85, p<0.05) and an over 3-fold higher hazard of death (adjusted HR=3.13, p<0.05). Among patients who achieved CCR or PR (n = 255), 78 patients achieved MRD- and 86 patients did not; 13(17%) patients who achieved MRD- and 23 (27%) patients who did not achieve MRD- progressed/died. Patients without MRD- had an over 2-fold higher hazard of progression/death (adjusted HR=2.11, p<0.05) compared to patients with MRD-. Overall survival was not significantly different among patients with an MRD assessment.Conclusion: Results from thisreal-world study suggest that among patients with R/R CLL, achieving deep response in second-line treatment is associated with improved PFS and OS. Given the findings from this study, achieving deep response should be considered as an endpoint for treatment in patients who are receiving first salvage therapy. [Display omitted] DisclosuresWierda:Genzyme: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; The University of Texas MD Anderson Cancer Center: Employment; Kite: Research Funding; GSK/Novartis: Consultancy, Honoraria, Research Funding; Acerta: Research Funding; Karyopharm: Research Funding; Merck: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Juno: Research Funding; Emergent: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria, Research Funding. Gauthier:AbbVie Inc.: Other: I am an employee of Analysis Group Inc., which received consulting fees from AbbVie for this study; Analysis Group, Inc: Employment. Meissner:AbbVie Inc.: Employment, Equity Ownership, Other: I am an employee of AbbVie, Inc and may own AbbVie and/or Abbott stock. Guerin:Analysis Group, Inc: Employment; Novartis: Other: I am an employee of Analysis Group, which received consulting fees from Novartis; AbbVie Inc.: Other: I am an employee of Analysis Group, which received consulting fees from AbbVie . Samp:AbbVie, Inc.: Employment, Equity Ownership, Other: I am an employee of AbbVie, Inc and may own AbbVie and/or Abbott stock.

Clinical Outcomes of Chronic Lymphocytic Leukemia (CLL) Patients with Richter's Transformation (RT) to Aggressive Non-Hodgkin Lymphoma (aNHL): a Single-Institution Experience

Background: Patients (pts) with RT from CLL have poor long-term outcomes with standard treatments. We examined the pt outcomes and the impact of different treatment options of standard therapy alone, standard therapy followed by autologous (autoSCT) or allogeneic stem cell transplant (alloSCT) or CAR-T cell therapy. Methods: Between 1998 and 2016, 47 pts were identified who had a diagnosis of CLL and transformed to aNHL. Multivariable models were used to test for independent predictors of overall survival (OS) by including the following factors: age at RT diagnosis, presence of del17p, high CD38, high ZAP-70, prior treatment for CLL (none/any), more than 2 treatments for CLL, ibrutinib therapy for CLL, complete response to first line of treatment for RT (CR1), autoSCT, alloSCT and CAR-T cell treatments for RT. Results: Median age at the time of RT diagnosis was 63 (35 - 91) years and 38% of pts were female. High risk CLL features included del17p (32%), del11q (15%), complex karyotype (11%), high CD38 (38%) and high ZAP-70 (28%). Fifteen pts (32%) had required no therapy for CLL before the RT diagnosis. Median number of CLL treatments was 1 (range: 0 -5). Most commonly used CLL treatments were fludarabine-based regimens (57%), bendamustine-based regimens (13%), ibrutinib (11%) and RCHOP (11%). Four percent had received alloSCT for CLL. Median time interval from CLL to RT diagnosis was 26 months (range 0 - 301). For RT therapy, pts received median three lines of treatment (range: 1 - 8). Fourteen pts (30%) achieved CR after first line treatment (CR1). CR1s were achieved using RCHOP (9), REPOCH (4) and HyperCVAD (1). Five patients (11%) received autoSCT only, 7 (15%) had alloSCT only and 7 (15%) received autoSCT followed by alloSCT. Six (13%) had treatment with CAR-T cells. Two of the CAR-T pts also had an autoSCT (1 before and 1 after) and 2 had alloSCT (both before CAR-T treatment). Median follow-up after RT diagnosis was 15 months (0.9 - 150) and median OS was 23.8 months (range 0.9 - 150). Overall, 3-year-OS was 47% (95% CI: 32-60). The 3-year OS rate was significantly higher in patients who achieved CR1: 86% (95% CI: 54-96) vs. 30% (95% CI: 16-46); p =.001. Among pts with CR1, 6 patients subsequently received transplant (autoSCT only= 1, alloSCT only=2, both =3) and all these pts were alive after median follow-up of 43 months (range: 20 -132). Outcome of these pts was not statistically different from those in CR1 who did not have a subsequent transplant (n=8) and had a 3-year OS of 75% (95% CI 31-93); p = .20. On the other hand, in patients who did not achieve CR1, there was a trend towards a better 3-year OS in patients who subsequently received transplant (autoSCT only=3, alloSCT only=6, both, =4) compared to those who did not (n=20): 46% (95% CI: 19-49) vs. 20% (95% CI: 6 -39); p = .05. Among all patients and in a multivariable model, only achievement of CR1 (HR 0.13; p .003) and having an alloSCT (HR 0.28; p 0.02) were associated with an improved OS. Among patients who did not achieve CR1 and in the multivariate analysis, there was a trend for improved OS only in patients who received an alloSCT (HR 0.35; p 0.06). Conclusion: Pts with RT have poor clinical outcome especially if they fail to achieve a CR after first line of treatment. Novel combinations are needed to increase the likelihood of achieving CR1. AlloSCT is associated with an improved OS in those pts and in RT pts in general and should be considered for treatment of RT pts. [Display omitted] DisclosuresShadman:Pharmacyclics: Other: advisory board, Research Funding; TG Therapeutics: Research Funding; Celgene: Research Funding; Acerta Pharma: Research Funding; Genentech: Consultancy, Research Funding; Merck: Research Funding; PLEXXIKON: Research Funding; Gilead: Research Funding; Emergent: Research Funding; AbbVie: Other: advisory board. Till:Genentech: Research Funding; Mustang Bio: Patents & Royalties, Research Funding. Holmberg:Seattle Genetics: Research Funding; Sanofi: Research Funding; Merck: Research Funding; Millennium: Research Funding; JAZZ: Consultancy; Up To Date: Patents & Royalties. Maloney:Celgene: Other: Advisory board; Juno Theraapeutics: Other: Advisory board, Patents & Royalties, Research Funding; Roche/Genetech: Other: Advisory board; Kite Pharmaceuticals: Other: Advisory board. Gopal:Seattle Genetics: Consultancy, Research Funding. Press:Roche: Honoraria, Research Funding; BMS: Honoraria; Bayer: Consultancy. Smith:Genentech: Research Funding; Merck: Research Funding; Acerta: Research Funding; Sharp: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Dohme Corp: Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding.

The Effect of Immune Checkpoint Inhibitors in Patients with Concomitant Advanced Melanoma and Chronic Lymphocytic Leukaemia

Immune checkpoint inhibitors (ICI's) have revolutionized the management of patients with advanced melanoma (AM). However, the data on the effectiveness of ICI's has been largely restricted to patients on clinical trials, thus excluding patients with second malignancies. Chronic Lymphocytic Leukemia (CLL) is the most prevalent adult leukemia and is associated immune dysregulation and a 3.8 fold increase in melanoma incidence. We report a multi-center, retrospective case-control study examining differences between patients who received checkpoint therapy in the context of the dual diagnoses of CLL and advanced melanoma (n = 20) compared to those with advanced melanoma alone (n = 154).Prognostic features for AM (including age, brain metastasis, visceral involvement, LDH and neutrophil count) were comparable between the two cohorts, however absolute lymphocyte count (ALC) was higher in CLL patients (p <0.0001) as anticipated. 3/20 of the CLL cohort experienced haematological autoimmune adverse events (AIHA, ITP, HLH), which necessitated cessation of ICI therapy; these events were not reported in the non-CLL cohort.There was not a significant difference between response rates to ICI's, 1-year survival or overall survival between CLL and non-CLL cohorts (Fig 1A). All recorded mortality (8/8) in the CLL cohort was attributable to AM progression or complications of ICI therapy rather than progressive CLL. The most significant predictor of survival in CLL cohort was prior exposure to fludarabine which showed a significantly shorter OS (median 2.3 vs 29.23 months, HR 7.406, p < 0.0001) than those who had not (Fig 1B).This cohort also offers a unique opportunity to observe the effects of ICI therapy on the progression of CLL. To our knowledge, this is the largest reported cohort of CLL patients treated with checkpoint inhibitors to date. The diagnosis of CLL pre-dated the diagnosis of AM in 18/20 cases. 5 cases had required prior treatment for CLL, while the remaining 15 cases were under observation alone. All 20 cases were Stage 0-1 according to the Rai classification at the time of melanoma diagnosis and no cases demonstrated a transformation to an aggressive subtype. 0/20 cases experienced a haematological response of their CLL while on ICI therapy and 6/20 cases progressed clinically either on the basis of tumour burden or absolute lymphocyte count within 12 months of ICI therapy (Fig 1C).This retrospective data demonstrates that ICI's have equivalent therapeutic efficacy in AM in patient with concurrent CLL This was unexpected as it was anticipated that the immune dysregulation associated with CLL would impair the ICI-mediated anti melanoma immunological response. The exception to this trend, was the poor efficacy of ICI's in patients with prior fludarabine exposure, presumably owing to the profound T cell depletion associated with this therapy. Additionally, ICI therapy alone appears ineffective in the management of CLL in keeping with recent phase II trial data. [Display omitted] DisclosuresGill:Janssen: Consultancy, Honoraria, Other: travel expenses.