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A placebo-controlled study of idelalisib in patients with relapsed chronic lymphocytic leukemia who were receiving rituximab was stopped early because of significant improvement in rates of response, progression-free survival, and overall survival with idelalisib. Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia among adults. Standard treatments include combinations of purine analogues, alkylating agents, and monoclonal antibodies. In younger patients without major coexisting illnesses, these regimens can provide high response rates of durable length but have substantial toxic effects. As a result, these treatments often have unacceptable side effects in older patients and those with coexisting illnesses. 1 Patients with relapsed CLL often have limited options because of the development of resistance to, or persisting toxic effects of, previous therapies. This is particularly true for elderly patients and those with coexisting illnesses. 2 For these patients, . . .

Tumor lysis syndrome (TLS) has been described in over 40% of patients with chronic lymphocytic leukemia treated with the cyclin-dependent kinase inhibitor, flavopiridol. We conducted a retrospective analysis to determine predictive factors for TLS. In 116 patients, the incidence of TLS was 46% (95% CI: 36–55%). In univariable analysis, female gender, greater number of prior therapies, Rai stages III–IV, adenopathy ⩾10 cm, splenomegaly, del(11q), decreased albumin and increased absolute lymphocyte count, white blood cell count (WBC), β2-microglobulin, and lactate dehydrogenase were associated ( P <0.05) with TLS. In multivariable analysis, female gender, adenopathy ⩾10 cm, elevated WBC, increased β2-microglobulin, and decreased albumin were associated with TLS ( P <0.05). With respect to patient outcomes, 49 and 44% of patients with and without TLS, respectively, responded to flavopiridol ( P =0.71). In a multivariable analysis, controlling for number of prior therapies, cytogenetics, Rai stage, age and gender, progression-free survival (PFS) was inferior in patients with TLS ( P =0.01). Female patients and patients with elevated β2-microglobulin, increased WBC, adenopathy ⩾10 cm and decreased albumin were at highest risk and should be monitored for TLS with flavopiridol. TLS does not appear to be predictive of response or improved PFS in patients receiving flavopiridol.

Data on pathologic changes of the 2019 novel coronavirus disease (COVID-19) are scarce. To gain knowledge about the pathology that may contribute to disease progression and fatality, we performed postmortem needle core biopsies of lung, liver, and heart in four patients who died of COVID-19 pneumonia. The patients’ ages ranged from 59 to 81, including three males and one female. Each patient had at least one underlying disease, including immunocompromised status (chronic lymphocytic leukemia and renal transplantation) or other conditions (cirrhosis, hypertension, and diabetes). Time from disease onset to death ranged from 15 to 52 days. All patients had elevated white blood cell counts, with significant rise toward the end, and all had lymphocytopenia except for the patient with leukemia. Histologically, the main findings are in the lungs, including injury to the alveolar epithelial cells, hyaline membrane formation, and hyperplasia of type II pneumocytes, all components of diffuse alveolar damage. Consolidation by fibroblastic proliferation with extracellular matrix and fibrin forming clusters in airspaces is evident. In one patient, the consolidation consists of abundant intra-alveolar neutrophilic infiltration, consistent with superimposed bacterial bronchopneumonia. The liver exhibits mild lobular infiltration by small lymphocytes, and centrilobular sinusoidal dilation. Patchy necrosis is also seen. The heart shows only focal mild fibrosis and mild myocardial hypertrophy, changes likely related to the underlying conditions. In conclusion, the postmortem examinations show advanced diffuse alveolar damage, as well as superimposed bacterial pneumonia in some patients. Changes in the liver and heart are likely secondary or related to the underlying diseases.

Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated ( p  < 0.001). Untreated patients had a lower risk of death (HR = 0.54, 95% CI:0.41–0.72). The risk of death was higher for older patients and those suffering from cardiac failure (HR = 1.03, 95% CI:1.02–1.04; HR = 1.79, 95% CI:1.04–3.07, respectively). Age, CLL-directed treatment, and cardiac failure were significant risk factors of OS. Untreated patients had a better chance of survival than those on treatment or recently treated.

Abstract Background Ibrutinib is a Bruton tyrosine kinase inhibitor that is used for the treatment of lymphoid cancers, including chronic lymphocytic leukemia, Waldenström macroglobulinemia, and mantle cell lymphoma. Several case series have described opportunistic infections among ibrutinib recipients, but the full extent of these infections is unknown. We sought to determine the spectrum of serious infections associated with ibrutinib treatment. Methods We reviewed the electronic medical records of patients with lymphoid cancer at Memorial Sloan Kettering Cancer Center who received ibrutinib during a 5-year period from 1 January 2012 to 31 December 2016. Serious infections were identified by review of the relevant microbiology, clinical laboratory, and radiology data. Risk factors for infection were determined by means of univariate and multivariate analyses. Results We analyzed findings in 378 patients with lymphoid cancer who received ibrutinib. The most common underlying cancers were chronic lymphocytic leukemia and mantle cell lymphoma. 84% of patients received ibrutinib as monotherapy. Serious infection developed in 43 patients (11.4%), primarily during the first year of ibrutinib treatment. Invasive bacterial infections developed in 23 (53.5%) of these patients, and invasive fungal infections (IFIs) in 16 (37.2%) .The majority of patients with IFIs during ibrutinib therapy (62.5%) lacked classic clinical risk factors for fungal infection (ie, neutropenia, lymphopenia, and receipt of corticosteroids). Infection resulted in death in 6 of the 43 patients (14%). Conclusions Patients with lymphoid cancer receiving ibrutinib treatment are at risk for serious infections, including IFIs. We reviewed the spectrum of serious infections among 378 patients with lymphoid cancer who received treatment with ibrutinib, a Bruton tyrosine kinase inhibitor. Serious infection occurred in 43 (11.4%) of the patients, invasive fungal infections in 16 (37.2%).

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, characterized by immunodeficiency. Hence, patients with CLL might be considered more susceptible to severe complications from COVID-19. We undertook this retrospective international multicenter study to characterize the course of COVID-19 in patients with CLL and identify potential predictors of outcome. Of 190 patients with CLL and confirmed COVID-19 diagnosed between 28/03/2020 and 22/05/2020, 151 (79%) presented with severe COVID-19 (need of oxygen and/or intensive care admission). Severe COVID-19 was associated with more advanced age (≥65 years) (odds ratio 3.72 [95% CI 1.79–7.71]). Only 60 patients (39.7%) with severe COVID-19 were receiving or had recent (≤12 months) treatment for CLL at the time of COVID-19 versus 30/39 (76.9%) patients with mild disease. Hospitalization rate for severe COVID-19 was lower (p < 0.05) for patients on ibrutinib versus those on other regimens or off treatment. Of 151 patients with severe disease, 55 (36.4%) succumbed versus only 1/38 (2.6%) with mild disease; age and comorbidities did not impact on mortality. In CLL, (1) COVID-19 severity increases with age; (2) antileukemic treatment (particularly BTK inhibitors) appears to exert a protective effect; (3) age and comorbidities did not impact on mortality, alluding to a relevant role of CLL and immunodeficiency.

Infections have become the major cause of morbidity and mortality among patients with chronic lymphocytic leukemia (CLL) due to immune dysfunction and cytotoxic CLL treatment. Yet, predictive models for infection are missing. In this work, we develop the CLL Treatment-Infection Model (CLL-TIM) that identifies patients at risk of infection or CLL treatment within 2 years of diagnosis as validated on both internal and external cohorts. CLL-TIM is an ensemble algorithm composed of 28 machine learning algorithms based on data from 4,149 patients with CLL. The model is capable of dealing with heterogeneous data, including the high rates of missing data to be expected in the real-world setting, with a precision of 72% and a recall of 75%. To address concerns regarding the use of complex machine learning algorithms in the clinic, for each patient with CLL, CLL-TIM provides explainable predictions through uncertainty estimates and personalized risk factors. Chronic lymphocytic leukemia is an indolent disease, and many patients succumb to infection rather than the direct effects of the disease. Here, the authors use medical records and machine learning to predict the patients that may be at risk of infection, which may enable a change in the course of their treatment.

Melanoma is the fifth most common cancer in the United States. The advent of immunotherapy and molecular targeted therapy has improved progression-free and overall survival in many patients with advanced disease. However, the selection of therapeutic choices requires a nuanced approach, especially when considering molecularly targeted agents. This case report highlights a diagnostic and therapeutic challenge in managing a patient with a history of chronic lymphocytic leukemia (CLL) and recurrent melanoma. Molecular testing suggested discordant BRAF V600E testing and a simultaneous NRAS G12D mutation. After a careful literature review, repetition of his molecular testing, and analysis of the timelines and results of all his molecular testing, we concluded that the BRAF V600E mutation result was falsely positive. The patient was treated with two cycles of ipilimumab (1 mg/kg) and nivolumab (3 mg/kg) as per the NADINA trial and had a complete radiographic response. He then underwent resection demonstrating a pathologic partial response ranging from 20% to 95% tumor necrosis, dependent on the satellite examined. This case report underscores the importance of precise molecular diagnostics in guiding melanoma treatment and demonstrates the complexities of managing a patient with a coexisting malignancy.

Bruton's tyrosine kinase inhibitors (BTKis) are central to the medical management of chronic lymphocytic leukemia. However, accumulating data suggest an important association with cardiovascular (CV) adverse events (AEs), including arrhythmias, hypertension, and bleeding, in patients with chronic lymphocytic leukemia and other hematological malignancies treated with this therapeutic class. Data from comparative trials with BTKis suggest second-generation agents, for example, acalabrutinib and zanubrutinib, may be associated with fewer CV AEs than first-in-class BTKi ibrutinib. PubMed and the proceedings of key hematology congresses were searched for relevant information using broad search terms, including chronic lymphocytic leukemia, BTKi, and toxicity. When managing patients with chronic lymphocytic leukemia, screening before and during treatment to assess CV risk is suggested to guide decision-making. Due to the increased toxicity with ibrutinib, the second-generation BTKis are now preferred (per the NCCN Clinical Practice Guidelines in Oncology [NCCN Guidelines]). For patients with a high CV risk, the decision between second-generation BTKi or a time-limited alternative, like venetoclax plus an anti-CD20 monoclonal antibody, should be made on an individual basis after patient consultation and consideration of the presenting characteristics of chronic lymphocytic leukemia in any given patient. The management of anticoagulant/antiplatelet medication during BTKi treatment requires specific attention, with coexistent medications being carefully assessed before starting a BTKi to reduce the risk of bleeding. For patients with a new-onset or worsening CV events during BTKi therapy, management may involve temporarily stopping the BTKi or switching to another class of therapy. To ensure the best outcomes, a collaborative care approach is essential, and some patients may need to be referred to a cardiologist/cardio-oncologist for specialist management. Baseline and ongoing CV risk assessment, careful monitoring, management, and a multidisciplinary team approach are all critical to ensure optimal oncologic and CV outcomes for patients with chronic lymphocytic leukemia receiving BTKis.