Novel combination approaches with targeted agents in frontline chronic lymphocytic leukemia.

Targeted therapies have revolutionized the frontline treatment landscape for patients with chronic lymphocytic leukemia (CLL) and have largely displaced a reliance on chemoimmunotherapy when treating this disease. Multiple randomized trials have documented the efficacy of oral therapy with the Bruton tyrosine kinase inhibitors ibrutinib and acalabrutinib (and zanubrutinib, pending a supplemental new drug application in CLL), as well as BCL2 inhibition using venetoclax. In this review, the authors highlight novel therapeutic strategies for using these agents in combination, either as doublet therapy or as triplet therapy, with anti-CD20 antibodies. First, the current treatment landscape is outlined, and the data are reviewed for continuous and time-limited therapeutic approaches, which constitute the current standard of care. Then, more recent reports are described from phase 2 and 3 studies exploring different combination strategies of Bruton tyrosine kinase and BCL2 inhibition for treatment-naive patients. In addition, relevant differences are emphasized between patient characteristics (e.g., patient fitness and the presence of high-risk disease features) and study methodology (e.g., dosing schedule, randomization, and assessment of measurable residual disease) across trials. Finally, the authors revisit the currently available data for these approaches in the context of ongoing studies and future planned trials, evaluating their potential impact on the frontline treatment landscape for CLL in the years to come.

Partial reconstitution of humoral immunity and fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib.

Chronic lymphocytic leukemia (CLL) is characterized by immune dysregulation, often including hypogammaglobulinemia, which contributes to a high rate of infections and morbidity. Ibrutinib, a covalent inhibitor of Bruton tyrosine kinase (BTK), inhibits B-cell receptor signaling and is an effective, US Food and Drug Administration (FDA)-approved treatment of CLL. Inactivating germline mutations in BTK cause a severe B-cell defect and agammaglobulinemia. Therefore, we assessed the impact of ibrutinib on immunoglobulin levels, normal B cells, and infection rate in patients with CLL treated with single-agent ibrutinib on a phase 2 investigator-initiated trial. Consistent with previous reports, immunoglobulin G (IgG) levels remained stable during the first 6 months on treatment, but decreased thereafter. In contrast, there were a transient increase in IgM and a sustained increase in IgA (median increase 45% at 12 months, P < .0001). To distinguish the effects on clonal B cells from normal B cells, we measured serum free light chains (FLCs). In κ-clonal CLL cases, clonal (κ) FLCs were elevated at baseline and normalized by 6 months. Nonclonal (λ) FLCs, which were often depressed at baseline, increased, suggesting the recovery of normal B cells. Consistently, we observed normal B-cell precursors in the bone marrow and an increase in normal B-cell numbers in the peripheral blood. Patients with superior immune reconstitution, as defined by an increase in serum IgA of ≥50% from baseline to 12 months, had a significantly lower rate of infections (P = .03). These data indicate that ibrutinib allows for a clinically meaningful recovery of humoral immune function in patients with CLL. This trial was registered at www.clinicaltrials.gov as #NCT015007330.

Risk Factors for Catheter Associated Urinary Tract Infections in a Pediatric Institution.

PURPOSE: Catheter associated urinary tract infections are an essential measure for health care quality improvement that affects reimbursement through hospital acquired condition reduction programs in adult patients. With the mounting importance of preventing such infections we evaluated risk factors for acquiring catheter associated urinary tract infections in pediatric patients. MATERIALS AND METHODS: All catheter associated urinary tract infections were identified at 1 pediatric institution from September 2010 to August 2014 from a prospective database maintained by the infection control office. To identify risk factors patients with a catheter associated urinary tract infection were individually matched to control patients with a urinary catheter but without infection by age, gender, date and the hospital location of the infection in 1:2 fashion. RESULTS: A total of 50 patients with catheter associated urinary tract infection were identified and matched to 100 control patients. Compared to controls the patients with infection were more likely to have a catheter in place for longer (2.9 days, OR 1.08, 95% CI 1.01, 1.15, p = 0.02). They were also more likely to be on contact precautions (OR 4.00, 95% CI 1.73, 9.26, p = 0.001), and have concurrent infections (OR 3.04, 95% CI 1.39, 6.28, p = 0.005) and a history of catheterization (OR 3.24, 95% CI 1.55, 6.77, p = 0.002). Using a conditional multivariate regression model the 3 most predictive variables were duration of catheter drainage, contact isolation status and history of catheterization. CONCLUSIONS: Longer duration of urinary catheter drainage, positive contact precautions status and a history of catheterization appear to be associated with a higher risk of catheter associated urinary tract infection in hospitalized pediatric patients. Physicians should attempt to decrease the duration of catheterization, especially in patients who meet these criteria, to minimize the risk of catheter associated urinary tract infection.

Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial.

BACKGROUND: Patients with chronic lymphocytic leukaemia (CLL) with TP53 aberrations respond poorly to first-line chemoimmunotherapy, resulting in early relapse and short survival. We investigated the safety and activity of ibrutinib in previously untreated and relapsed or refractory CLL with TP53 aberrations. METHODS: In this investigator-initiated, single-arm phase 2 study, we enrolled eligible adult patients with active CLL with TP53 aberrations at the National Institutes of Health Clinical Center (Bethesda, MD, USA). Patients received 28-day cycles of ibrutinib 420 mg orally once daily until disease progression or the occurrence of limiting toxicities. The primary endpoint was overall response to treatment at 24 weeks in all evaluable patients. This study is registered with ClinicalTrials.gov, number NCT01500733, and is fully enrolled. FINDINGS: Between Dec 22, 2011, and Jan 2, 2014, we enrolled 51 patients; 47 had CLL with deletion 17p13.1 and four carried a TP53 mutation in the absence of deletion 17p13.1. All patients had active disease requiring therapy. 35 enrolled patients had previously untreated CLL and 16 had relapsed or refractory disease. Median follow-up was 24 months (IQR 12.9-27.0). 33 previously untreated patients and 15 patients with relapsed or refractory CLL were evaluable for response at 24 weeks. 32 (97%; 95% CI 86-100) of 33 previously untreated patients achieved an objective response, including partial response in 18 patients (55%) and partial response with lymphocytosis in 14 (42%). One patient had progressive disease at 0.4 months. 12 (80%; 95% CI 52-96) of the 15 patients with relapsed or refractory CLL had an objective response: six (40%) achieved a partial response and six (40%) a partial response with lymphocytosis; the remaining three (20%) patients had stable disease. Grade 3 or worse treatment-related adverse events were neutropenia in 12 (24%) patients (grade 4 in one [2%] patient), anaemia in seven (14%) patients, and thrombocytopenia in five (10%) patients (grade 4 in one [2%] patient). Grade 3 pneumonia occurred in three (6%) patients, and grade 3 rash in one (2%) patient. INTERPRETATION: The activity and safety profile of single-agent ibrutinib in CLL with TP53 aberrations is encouraging and supports its consideration as a novel treatment option for patients with this high-risk disease in both first-line and second-line settings. FUNDING: Intramural Research Program of the National Heart, Lung, and Blood Institute and the National Cancer Institute, Danish Cancer Society, Novo Nordisk Foundation, National Institutes of Health Medical Research Scholars Program, and Pharmacyclics Inc.

Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib.

Ibrutinib is associated with bleeding-related adverse events of grade ≤ 2 in severity, and infrequently with grade ≥ 3 events. To investigate the mechanisms of bleeding and identify patients at risk, we prospectively assessed platelet function and coagulation factors in our investigator-initiated trial of single-agent ibrutinib for chronic lymphocytic leukemia. At a median follow-up of 24 months we recorded grade ≤ 2 bleeding-related adverse events in 55% of 85 patients. No grade ≥ 3 events occurred. Median time to event was 49 days. The cumulative incidence of an event plateaued by 6 months, suggesting that the risk of bleeding decreases with continued therapy. At baseline, von Willebrand factor and factor VIII levels were often high and normalized on treatment. Platelet function measured via the platelet function analyzer (PFA-100™) was impaired in 22 patients at baseline and in an additional 19 patients on ibrutinib (often transiently). Collagen and adenosine diphosphate induced platelet aggregation was tested using whole blood aggregometry. Compared to normal controls, response to both agonists was decreased in all patients with chronic lymphocytic leukemia, whether on ibrutinib or not. Compared to untreated chronic lymphocytic leukemia patients, response to collagen showed a mild further decrement on ibrutinib, while response to adenosine diphosphate improved. All parameters associated with a significantly increased risk of bleeding-related events were present at baseline, including prolonged epinephrine closure time (HR 2.74, P=0.012), lower levels of von Willebrand factor activity (HR 2.73, P=0.009) and factor VIII (HR 3.73, P=0.0004). In conclusion, both disease and treatment-related factors influence the risk of bleeding. Patients at greater risk for bleeding of grade ≤ 2 can be identified by clinical laboratory tests and counseled to avoid aspirin, non-steroidal anti-inflammatory drugs and fish oils. ClinicalTrials.gov identifier NCT01500733.

Measurable Residual Disease Monitoring in Lymphoma.

PURPOSE OF REVIEW: The utility of analyzing circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and disease in the bone marrow as an adjunctive tool in caring for hematologic cancer patients is expanding. This holds true for lymphoma where these biomarkers are being explored as a means of genotyping and quantifying disease. Regarding the latter, they can be used to monitor measurable residual disease (MRD) during and after treatment. This holds potential for aiding clinical decisions amidst treatment, detecting earlier relapse, and improving prognostication. Here, we review the evidence to support these applications in a variety of lymphoma subtypes. RECENT FINDINGS: Numerous clinical trials across a variety of lymphomas have demonstrated value in MRD monitoring. MRD monitoring is often prognostic for progression free survival (PFS) and even overall survival (OS) at several time points in a disease course, particularly when utilizing serial measurements. With regards to tailoring treatment, there are a growing number of trials examining MRD-adaptive treatment strategies to intensify or de-escalate treatment to individualize care. Lastly, MRD monitoring has been utilized successfully in detecting earlier relapse when compared to more standard methods of clinical surveillance such as radiographic assessment. Although not routinely implemented into clinical practice, MRD monitoring in lymphoma is helping shape the future landscape of this disease by aiding in prognostication, guiding therapy, and detecting earlier relapse. Steps to standardize and further examine this technology prospectively are being taken to bring MRD monitoring to the forefront of the field.

Targeting CD38 with Daratumumab Plus Chemotherapy for Patients with Advanced-Stage Plasmablastoid Large B-Cell Lymphoma.

Plasmablastic lymphoma (PBL) is a rare and aggressive form of large B-cell lymphoma (LBCL) most commonly seen in the setting of chronic immunosuppression or autoimmune disease. The prognosis is poor and CHOP-like regimens often fail to produce durable remission; therefore, there is no established standard of care treatment. However, PBL demonstrates substantial morphologic and immunophenotypic overlap with multiple myeloma (MM), suggesting that MM therapeutics might prove useful in treating PBL. We studied the effects of treatment using the first-in-class monoclonal antibody directed against CD38, daratumumab, in combination with chemotherapy in seven patients with advanced-stage LBCL with plasmablastic features. Treatment was safe and well-tolerated. Among six evaluable patients, six patients had complete response after treatment, and four patients who met strict WHO criteria for PBL had durable response (12-31 months and ongoing).

Asymptomatic enlargement of the clavicle: a review of underlying aetiologies.

An asymptomatic enlargement of the medial clavicle is a condition that is often both missed and misdiagnosed. We review the most common causes of an isolated and asymptomatic enlargement of the medial clavicle. Underlying aetiologies include osteoarthritis of the sternoclavicular joint, condensing osteitis, spontaneous dislocation of the sternoclavicular joint, and sternocostoclavicular hyperostosis. Key points in the history and physical examination as well as characteristic radiographic findings are sufficient for correct diagnoses. Treatment is conservative.

Managing toxicities of Bruton tyrosine kinase inhibitors.

Inhibition of Bruton's tyrosine kinase (BTK) has revolutionized the treatment landscape for patients with chronic lymphocytic leukemia (CLL). By targeting this critical kinase in proximal B-cell receptor signaling, BTK inhibitors (BTKis) impair cell proliferation, migration, and activation of NF-κB. Clinically, because indefinite inhibition is a mainstay of therapy, there is an extended period of exposure in which adverse effects can develop. Given the impressive efficacy and activity of BTKis in the treatment of patients with CLL, appropriate management of treatment-emergent adverse events (AEs) is of paramount importance. Here we review the BTKi landscape and present the available toxicity and safety data for each agent. The long-term toxicity profile of ibrutinib, a first-in-class inhibitor, is well characterized and includes a clinically significant incidence of cardiac arrhythmias, bleeding, infection, diarrhea, arthralgias, and hypertension. Acalabrutinib, the initial second-generation BTKi to earn approval from the US Food and Drug Administration, demonstrates improved kinase selectivity for BTK, with commonly observed adverse reactions including infection, headache, and diarrhea. Mediated by both on-target inhibition of BTK and variable off-target inhibition of other kinases including interleukin-2-inducible T-cell kinase (ITK), tyrosine-protein kinase (TEC), and endothelial growth factor receptor (EGFR), the toxicity profile of BTKis is closely linked to their pattern of kinase binding. Other emerging BTKis include second-generation agents with variable degrees of kinase selectivity and third-generation agents that exhibit reversible noncovalent binding to BTK. We also highlight critical considerations for the prevention and monitoring of AEs and offer practical management strategies for treatment-emergent toxicities.

Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring.

In many areas of oncology, we lack sensitive tools to track low-burden disease. Although cell-free DNA (cfDNA) shows promise in detecting cancer mutations, we found that the combination of low tumor fraction (TF) and limited number of DNA fragments restricts low-disease-burden monitoring through the prevailing deep targeted sequencing paradigm. We reasoned that breadth may supplant depth of sequencing to overcome the barrier of cfDNA abundance. Whole-genome sequencing (WGS) of cfDNA allowed ultra-sensitive detection, capitalizing on the cumulative signal of thousands of somatic mutations observed in solid malignancies, with TF detection sensitivity as low as 10-5. The WGS approach enabled dynamic tumor burden tracking and postoperative residual disease detection, associated with adverse outcome. Thus, we present an orthogonal framework for cfDNA cancer monitoring via genome-wide mutational integration, enabling ultra-sensitive detection, overcoming the limitation of cfDNA abundance and empowering treatment optimization in low-disease-burden oncology care.

Biology of chronic lymphocytic leukemia in different microenvironments: clinical and therapeutic implications.

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature monoclonal B cells in peripheral blood, bone marrow, spleen, and lymph nodes. The trafficking, survival, and proliferation of CLL cells is tightly regulated by the surrounding tissue microenvironment and is mediated by antigenic stimulation, close interaction with various accessory cells and exposure to different cytokines, chemokines, and extracellular matrix components. In the last decade there have been major advances in the understanding of the reciprocal interactions between CLL cells and the various microenvironmental compartments. This article discusses the role of the microenvironment in the context of efforts to develop novel therapeutics that target the biology of CLL.

Dermatologic presentations of orthopedic pathologies: a review of diagnosis and treatment.

Dermatologic presentations of orthopedic diseases are commonly encountered in the dermatology clinic. These disorders often necessitate prompt recognition in order to properly refer for definitive treatment as well as to avoid unnecessary diagnostic procedures. As such, the presentations of these diseases as well as the treatments available deserve special attention. This review aims to identify orthopedic diseases with dermatologic presentations and discuss the diagnosis and treatment of these pathologies. In conducting this review, a comprehensive literature search was conducted. Our inquiry was limited to conditions with a unitary orthopedic etiology. By excluding syndromic dysfunctions with both orthopedic and dermatologic manifestations, we were able to create a consistent approach to the review. At the same time, such exclusions created an omission of many important disease processes that require the cooperation of orthopedists and dermatologists. In all, 19 orthopedic disorders and disorder classes with dermatologic findings were identified and carefully examined. The orthopedic pathologies identified require varying diagnostic and therapeutic approaches. While some do not warrant further work-up or referral, the disease course of certain pathologies is drastically altered by timely recognition, cautious diagnostic interrogation, and prompt referral.