Citations

The authors documented a low compliance with guidelines to screen for skin malignancy in a community-dwelling cohort of patients with newly diagnosed chronic lymphocytic leukemia.

BACKGROUNDGeneral internists suffer higher rates of burnout and lower satisfaction with work‐life balance than most specialties, but the impact of inpatient vs outpatient practice location is unclear.METHODSPhysicians in the American Medical Association Physician Masterfile were previously surveyed about burnout, depression, suicidal ideation, quality of life, fatigue, work‐life balance, career plans, and health behaviors. We extracted and compared data for these variables for the 130 internal medicine hospitalists and 448 outpatient general internists who participated. Analyses were adjusted for age, sex, hours worked, and practice setting.RESULTSThere were 52.3% of the hospitalists and 54.5% of the outpatient internists affected by burnout (P = 0.86). High scores on the emotional exhaustion subscale (43.8% vs 48.1%, P = 0.71) and on the depersonalization subscale (42.3% vs 32.7%, P = 0.17) were common but similar in frequency in the 2 groups. Hospitalists were more likely to score low on the personal accomplishment subscale (20.3% vs 9.6%, P = 0.04). There were no differences in symptoms of depression (40.3% for hospitalists vs 40.0% for outpatient internists, P = 0.73) or recent suicidality (9.2% vs 5.8%, P = 0.15). Rates of reported recent work‐home conflict were similar (48.4% vs 41.3%, P = 0.64), but hospitalists were more likely to agree that their work schedule leaves enough time for their personal life and family (50.0% vs 42.0%, P = 0.007).CONCLUSIONSBurnout was common among both hospitalists and outpatient general internists, although hospitalists were more satisfied with work‐life balance. A better understanding of the causes of distress and identification of solutions for all internists is needed. Journal of Hospital Medicine 2014;9:176–181. © 2014 Society of Hospital Medicine

Abstract Ofatumumab (OFA), a human CD20-targeting mAb, kills B lymphocytes using the innate immune system including complement-dependent cytotoxicity (CDC). The efficacy of OFA in patients with chronic lymphocytic leukemia (CLL) is limited by drug resistance, which is not well characterized. To better understand mechanisms of resistance, we prospectively studied CLL cells isolated from blood samples collected before and after in vivo exposure to the initial dose of OFA therapy in 25 patients undergoing their first treatment for progressive CLL. As previously reported, OFA therapy rapidly decreased the absolute lymphocyte count, CD20 expression by CLL cells, and serum complement levels. We now show that after administration of the first dose of OFA, there was a modest rebound in the absolute lymphocyte count and serum complement levels, but substantial ongoing loss of CD20 expression by CLL cells. These post-OFA treatment CLL cells were highly resistant to OFA-mediated CDC but retained sensitivity to alemtuzumab-mediated CDC in vitro. Posttherapy serum OFA levels correlated inversely with both the amount of pretreatment circulating cell-bound CD20 and with the decrease in this value following treatment. In vitro OFA-mediated CDC did not predict clinical responses, and the patients with first-dose reactions to OFA did not have markers of increased complement activation in vivo. We propose that optimal efficacy of CD20- targeted therapy for CLL requires determining an mAb dose size and frequency that optimizes CLL killing without exceeding the capacity of the cytotoxic mechanisms and thus minimizes loss of CD20 expression in the surviving CLL cells.

Richter syndrome (RS) is defined as the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). RS occurs in approximately 2% to 10% of CLL patients during the course of their disease, with a transformation rate of 0.5% to 1% per year. A combination of germline genetic characteristics, clinical features (eg, advanced Rai stage), biologic (ζ-associated protein-70+, CD38+, CD49d+) and somatic genetic (del17p13.1 or del11q23.1) characteristics of CLL B cells, and certain CLL therapies are associated with higher risk of RS. Recent studies have also identified the crucial role of CDKN2A loss, TP53 disruption, C-MYC activation, and NOTCH1 mutations in the transformation from CLL to RS. An excisional lymph node biopsy is considered the gold standard for diagnosis of RS; a 18F-fluorodeoxyglucose positron emission tomography scan can help inform the optimal site for biopsy. Approximately 80% of DLBCL cases in patients with CLL are clonally related to the underlying CLL, and the median survival for these patients is approximately 1 year. In contrast, the remaining 20% of patients have a clonally unrelated DLBCL and have a prognosis similar to that of de novo DLBCL. For patients with clonally related DLBCL, induction therapy with either an anthracycline- or platinum-based regimen is the standard approach. Postremission stem cell transplantation should be considered for appropriate patients. This article summarizes our approach to the clinical management of CLL patients who develop RS.

AbstractThe link between immunosuppression and skin cancer has been well described. The two most common situations involving immunosuppression‐associated skin cancer are solid organ transplantation and non‐Hodgkin lymphoma (NHL), including chronic lymphocytic leukemia (CLL). Patients with lymphoma are more likely to have development of a secondary malignancy, with skin cancer being the most common. The most common types of skin cancer in patients with NHL/CLL include melanoma, squamous cell carcinoma, basal cell carcinoma, and Merkel cell carcinoma. Many skin cancers demonstrate increased aggressiveness in patients with NHL/CLL and are associated with higher recurrence rates, increased regional metastasis, and death secondary to skin cancer metastases. This review delineates the current research regarding the relationship between NHL/CLL and cutaneous malignancy. Immunosuppressed patients with skin cancer should be treated promptly and aggressively to decrease recurrence and metastases. Regular skin self‐examinations, dermatologic examinations, sun‐protective habits, and education may prove beneficial in this high‐risk patient population.

AbstractDespite the advanced age at onset, chronic lymphocytic leukemia (CLL) shortens the life expectancy of the majority of newly diagnosed patients. The management of elderly patients with CLL is more complex than that of younger patients due to the greater frequency of comorbidities and functional impairment as well as reduced organ function. Many of the recent advances in the care of CLL patients (prognostication, more intense combination therapy regimens) are of unclear relevance for elderly patients. This review addresses 5 key questions in the management of elderly patients with CLL: (1) why is classifying the “fitness” of CLL patients necessary; (2) what criteria should be used to classify patient fitness; (3) when should elderly patients be treated; (4) how should therapy be selected for elderly patients; and (5) which therapy is best (for this patient)?

SummaryDetection of a 17p13.1 deletion (loss of TP53) or 11q22.3 deletion (loss of ATM), by fluorescence in situ hybridization (FISH), in chronic lymphocytic leukaemia (CLL) patients is associated with a poorer prognosis. Because TP53 and ATM are integral to the TP53 pathway, we hypothesized that 17p13.1‐ (17p‐) and 11q22.3‐ (11q‐) occurring in the same cell (clonal 17p‐/11q‐) would confer a worse prognosis than either 17p‐ or 11q‐. We studied 2184 CLL patients with FISH (1995–2012) for the first occurrence of 17p‐, 11q‐, or clonal 17p‐/11q‐. Twenty (1%) patients had clonal 17p–/11q‐, 158 (7%) had 17p‐ (including 4 with 17p‐ and 11q‐ in separate clones), 247 (11%) had 11q‐, and 1759 (81%) had neither 17p‐ nor 11q‐. Eleven of 15 (73%) tested patients with clonal 17p‐/11q‐ had dysfunctional TP53 mutations. Overall survival for clonal 17p‐/11q‐ was significantly shorter (1·9 years) than 17p‐ (3·1 years, P = 0·04), 11q‐ (4·8 years, P ≤ 0·0001), or neither 17p‐ nor 11q‐ (9·3 years, P ≤ 0·0001). Clonal 17p‐/11q‐ thus conferred significantly worse prognosis, suggesting that loss of at least one copy of both TP53 and ATM causes more aggressive disease. Use of an ATM/TP53 combination FISH probe set could identify these very‐high risk patients.

BACKGROUNDAlthough rituximab‐based chemoimmunotherapy (CIT) has substantially improved clinical outcomes in chronic lymphocytic leukemia (CLL), only 40% to 50% of patients achieve a complete remission (CR). There remains interest in identifying new approaches to improve the effectiveness of CIT. Ofatumumab is a fully human anti‐CD20 monoclonal antibody with greater apparent single‐agent activity than rituximab in CLL patients.METHODSPreviously untreated CLL patients in need of therapy received 6 cycles of CIT induction with pentostatin, cyclophosphamide, and ofatumumab (PCO) followed by response assessment.RESULTSOf the 48 patients enrolled, 77% completed PCO induction. Adverse events during induction included grade 3+ hematologic toxicity (27%) and grade 3+ nonhematologic toxicity (23%). Median CD4 count after induction and 6 months later were 186 × 106/L and 272 × 106/L. The overall response rate was 96% (46 of 48 patients), and the CR rate was 46% (22 of 48 patients). Among the 38 patients who underwent minimal residual disease evaluation, 7 (18%) were negative for minimal residual disease. After median follow‐up of 24 months, 10 (21%) patients have progressed and 8 (17%) have required retreatment. The efficacy and toxicity of ofatumumab‐based CIT compare favorably to our historical trials of rituximab‐based CIT using an identical chemotherapy backbone (n = 64). Time to retreatment also appeared longer for ofatumumab‐based CIT (free of retreatment at 24 months: 86% [95% confidence interval = 75‐99] versus 68% [95% confidence interval = 56‐81] for rituximab‐based CIT).CONCLUSIONSOfatumumab‐based CIT is well tolerated in patients with previously untreated CLL. The efficacy of ofatumumab‐based CIT compares favorably to historical trials of rituximab‐based CIT, suggesting randomized trials comparing ofatumumab‐based CIT and rituximab‐based CIT should be considered. Cancer 2013;119:3788–3796. © 2013 American Cancer Society.

SummaryNearly all information about patients with chronic lymphocytic leukaemia (CLL) who develop diffuse large B‐cell lymphoma [Richter syndrome (RS)] is derived from retrospective case series or patients treated on clinical trials. We used the Mayo Clinic CLL Database to identify patients with newly diagnosed CLL between January 2000 and July 2011. Individuals who developed biopsy‐proven RS during follow‐up were identified. After a median follow‐up of 4 years, 37/1641 (2·3%) CLL patients developed RS. The rate of RS was approximately 0·5%/year. Risk of RS was associated with advanced Rai stage at diagnosis (P < 0·001), high‐risk genetic abnormalitites on fluorescence in situ hybridization (P < 0·0001), unmutated IGHV (P = 0·003), and expression of ZAP70 (P = 0·02) and CD38 (P = 0·001). The rate of RS doubled in patients after treatment for CLL (1%/year). Stereotyped B‐cell receptors (odds‐ratio = 4·2; P = 0·01) but not IGHV4‐39 family usage was associated with increased risk of RS. Treatment with combination of purine analogues and alkylating agents increased the risk of RS three‐fold (odds‐ratio = 3·26, P = 0·0003). Median survival after RS diagnosis was 2·1 years. The RS prognosis score stratified patients into three risk groups with median survivals of 0·5 years, 2·1 years and not reached. Both underlying characteristics of the CLL clone and subsequent CLL therapy influence the risk of RS. Survival after RS remains poor and new therapies are needed.