Real-world management of targeted therapies in chronic lymphocytic leukemia.

The advent of novel targeted therapies, including B-cell receptor (BCR) pathway and B-cell lymphoma 2 (BCL2) inhibitors, has substantially changed the treatment paradigm for chronic lymphocytic leukemia (CLL). Although targeted therapies have improved outcomes compared to traditional chemoimmunotherapy in the front-line and relapsed or refractory settings, they are associated with resistance mutations and suboptimal outcomes in certain high-risk patients. Additionally, targeted therapies are associated with drug interactions and unique adverse effect profiles which can be challenging for patients and clinicians to manage. Ongoing studies continue to address questions regarding optimal sequencing of therapies, the role of treatment combinations, and the efficacy of next-generation novel agents. This review provides a comprehensive overview regarding the clinical management of targeted therapies for CLL and applies current literature to clinical practice.

Tolerability and toxicity of pegaspargase in adults 40 years and older with acute lymphoblastic leukemia.

Pegaspargase is a modified version of asparaginase with prolonged asparagine depletion. It appears to be safe in adults <40 years old, but has a unique spectrum of toxicities, the risks of which appear to increase with age. The primary objective of this study was to evaluate pegaspargase tolerability and toxicity as assessed by evaluation of incidence and severity of adverse events. Secondary objectives included characterization of the reasons underlying pegaspargase discontinuation, when applicable. Grade 3/4 asparaginase-related toxicities with ≥10% incidence included: hyperbilirubinemia, hyperglycemia, hypertriglyceridemia, hypoalbuminemia, hypofibrinogenemia, and transaminitis. 63% of patients (38 of 60) received all intended doses of pegaspargase, with the most common reasons for discontinuation noted as hypersensitivity (12%), hyperbilirubinemia/transaminitis (8%), and hematopoietic transplantation in complete remission (10%). This study suggests that while hepatotoxicity and other known adverse effects are common, with careful monitoring, pegaspargase can safely be administered to adults with ALL age ≥40 years old.

Correlation of IL-6 secretion and hyponatremia with the use of CD19+ chimeric antigen receptor T-cells
.

BACKGROUND: Various studies have demonstrated that interleukin-6 (IL-6) activates the central magnocellular arginine vasopressin (AVP)-secreting neurons in the brain to produce non-osmotic, non-volume-mediated increases in AVP. The most common toxicity of CD19+ chimeric antigen receptor (CAR) T-cells is cytokine release syndrome, which is related to increased levels of IL-6. This study will evaluate the correlation of IL-6 levels with hyponatremia in patients receiving CD19+ CAR T-cells. MATERIALS AND METHODS: This is a single-center retrospective analysis of adult patients who received CD19+ CAR T-cells for the treatment of relapsed/refractory acute lymphoblastic leukemia (ALL). RESULTS: Hyponatremia, defined as a serum sodium (Na) ≤ 135 mEq/L, occurred in 31 (61%) patients. A change in Na > 7 mEq occurred in 32 (63%) patients, and the median lowest Na was 133 mEq/L (interquartile range (IQR): 131 - 136)). There was an inverse linear relationship between IL-6 levels and lowest Na (p = 0.001). Overall, per 10-fold increase in IL-6, Na decreased by an average of 2.68 mEq/L. CONCLUSION: Hyponatremia is common in patients who received CD19+ CAR T-cells. There is an inverse linear relationship between IL-6 levels and nadir Na (p = 0.001). Further studies will be needed to confirm a causative relationship between IL-6 levels and hyponatremia following CD19+ CAR T-cell infusion.

No Loose Ends: A Review of the Pharmacotherapy of Hairy Cell and Hairy Cell Leukemia Variant.

Objective: To review the literature for the treatment of classical and variant hairy cell leukemia (HCL, HCLv), evaluating efficacy, safety, and supportive care involved in the use of purine analogues (PAs), interferon, BRAF inhibitors, monoclonal antibodies, Bruton's tyrosine kinase inhibitors, and new immunotoxin, moxetumomab pasudotox-tdfk (MPT). An electronic literature search of PubMed (January 1958 to January 2019) was conducted in PubMed using the MESH terms hairy cell leukemia, hairy cell leukemia variant, cladribine, pentostatin, rituximab, interferon, vemurafenib, moxetumomab pasudotox. Study Selection and Data Extraction: Studies written in the English language were considered for this article. The significance of each article was determined by authors independently. Data Synthesis: HCL and HCLv are rare B-cell lymphoproliferative disorders, each with distinct biologies. Symptoms are characterized by pancytopenia and splenomegaly. Initial treatments for HCL were suboptimal, leading to minimal and transient remissions. PAs significantly improved outcomes, inducing remission in most patients. However, those with purine-resistant disease were left with a dearth of options, leading to implementation of vemurafenib for BRAF V600 mutated disease and chemoimmunotherapy with rituximab. Despite these advances, some HCL and a majority of HCLv patients experience relapse. Newer targeted agents offer promise for relapsed and refractory patients, including the recently approved MPT. Relevance to Patient Care and Clinical Practice: This review provides a comprehensive update on the pharmacological management of HCL and HCLv for clinicians who encounter patients with this rare disease. Conclusion: HCL and HCLv are uncommon lymphoid neoplasms that lead to a characteristic constellation of symptoms. The emergence of PAs and novel targeted agents have improved the likelihood and durability of responses for these patients.

Characteristics and outcomes of patients with hematologic malignancies receiving chemotherapy in the intensive care unit.

BACKGROUND: The objective of this study was to evaluate the short-term and long-term outcomes of adult patients with hematologic malignancies who received chemotherapy in the intensive care unit (ICU). METHODS: This was a retrospective, single-center study comparing the outcomes of patients with hematologic malignancies who received chemotherapy in the ICU with a matched cohort of ICU patients who did not receive chemotherapy. Conditional logistic regression and shared-frailty Cox regression were used to assess short-term (ICU and hospital) mortality and death by 12 months after hospital discharge, respectively. RESULTS: One hundred eighty-one patients with hematologic malignancies received chemotherapy in the ICU. The ICU and hospital mortality rates were 25% and 42% for chemotherapy patients and 22% and 33% for non-chemotherapy patients, respectively. Higher severity of illness scores on ICU admission were significantly associated with higher ICU mortality (odds ratio, 1.07; P < .001) and hospital mortality (odds ratio, 1.05; P ≤ .001). Six-month and 12-month survival estimates posthospital discharge were 58% and 50%, respectively. Compared with the matched cohort of patients who did not receive chemotherapy, those who did receive chemotherapy had a significantly longer length of stay in the ICU (median, 6 vs 3 days; P < .001) and in the hospital (median, 22 vs 14 days; P = .024). In multivariable analysis, the patients who received chemotherapy in the ICU had a trend toward a higher risk of dying by 12 months (hazard ratio, 1.45; P = .08). CONCLUSIONS: Short-term mortality was similar among patients with hematologic malignancies who did and did not receive chemotherapy in the ICU, although patients who received chemotherapy had increased resource utilization. These results may inform ICU triage and goals-of-care discussions with patients and their families regarding outcomes after receiving chemotherapy in the ICU. Cancer 2018;124:3025-36. © 2018 American Cancer Society.

The ABCs of Immunotherapy for Adult Patients With B-Cell Acute Lymphoblastic Leukemia.

OBJECTIVE: To review the pharmacology, efficacy, and safety of Food and Drug Administration approved and promising immunotherapy agents used in the treatment of acute lymphoblastic leukemia (ALL). DATA SOURCES: A literature search was performed of PubMed and MEDLINE databases (1950 to July 2017) and of abstracts from the American Society of Hematology and the American Society of Clinical Oncology. Searches were performed utilizing the following key terms: rituximab, blinatumomab, inotuzumab, ofatumumab, obinutuzumab, Blincyto, Rituxan, Gazyva, Arzerra, CAR T-cell, and chimeric antigen receptor (CAR). STUDY SELECTION/DATA EXTRACTION: Studies of pharmacology, clinical efficacy, and safety of rituximab, ofatumumab, obinutuzumab, inotuzumab, blinatumomab, and CAR T-cells in the treatment of adult patients with ALL were identified. DATA SYNTHESIS: Conventional chemotherapy has been the mainstay in the treatment of ALL, producing cure rates of approximately 90% in pediatrics, but it remains suboptimal in adult patients. As such, more effective consolidative modalities and novel therapies for relapsed/refractory disease are needed for adult patients with ALL. In recent years, anti-CD20 antibodies, blinatumomab, inotuzumab, and CD19-targeted CAR T-cells have drastically changed the treatment landscape of B-cell ALL. CONCLUSION: Outcomes of patients with relapsed disease are improving thanks to new therapies such as blinatumomab, inotuzumab, and CAR T-cells. Although the efficacy of these therapies is impressive, they are not without toxicity, both physical and financial. The optimal sequencing of these therapies still remains a question.

The use of Erwinia asparaginase for adult patients with acute lymphoblastic leukemia after pegaspargase intolerance.

Asparaginase administration has become a crucial component of front-line pediatric and pediatric-insipired multi-agent regimens for the treatment of acute lymphoblastic leukemia (ALL). The aim of this retrospective study was to assess the safety and feasibility of switching to Erwinia asparaginase after pegaspargase intolerance in adult ALL patients treated at Memorial Sloan Kettering Cancer Center. Our analysis included 10 patients, with a median age of 39 years (range 20-72), male predominance (90%), and a typical B-cell to T-cell ratio (70:30%) for ALL. Nine patients were switched to Erwinia asparaginase after pegaspargase hypersensitivity and one patient after grade 4 hyperbilirubinemia secondary to pegaspargase. With Erwinia asparaginase, no hypersensitivity reactions occurred and no patient developed other known clinical asparaginase-related toxicities. Laboratory adverse effects consisted of mostly mild elevation in liver enzymes. No morphologic relapses have occurred in any patient switched to Erwinia asparaginase in first remission at a follow up of 0.4-34.6 months. These findings are unique in that all of our patients received Erwinia asparaginase after hypersensitivity or intolerance to pegaspargase and 50% of them were older than 40 years of age, a population with very limited Erwinia asparaginase data. Our observations provide preliminary information that treatment with Erwinia asparaginase can proceed as scheduled in adult patients, despite pegaspargase hypersensitivity and possibly liver intolerance.

Blinatumomab: A First-in-Class Bispecific T-Cell Engager for Precursor B-Cell Acute Lymphoblastic Leukemia.

OBJECTIVE: To review the clinical pharmacology, efficacy, and safety of blinatumomab for the treatment of pediatric and adult precursor B-cell acute lymphoblastic leukemia (B-ALL). DATA SOURCES: A literature search of EMBASE (1947 to April 2015), Medline (1946 to April 2015), PubMed (1996 to April 2015), the U.S. National Institutes of Health Clinicaltrials.gov, the Food and Drug Administration, and relevant meeting abstracts was conducted using the terms blinatumomab, BiTE, bispecific T-cell engager, MT103, MEDI-538, and Blincyto. STUDY SELECTION/DATA EXTRACTION: Human and animal studies describing the pharmacology, pharmacokinetics and pharmacodynamics, efficacy, and safety of blinatumomab for precursor B-ALL were identified. DATA SYNTHESIS: Blinatumomab is a first-in-class bispecific T-cell engager (BiTE) antibody derived from a B-lineage specific antitumor mouse monoclonal antibody that binds to both CD19 of B-cells and CD3 of T-cells. A pivotal phase II trial demonstrated that response rates were high in a refractory or relapsed patient population, with 43% achieving complete remission (CR). Median relapse-free survival was 5.9 months for those with CR or CR with incomplete hematological recovery. Median overall survival was 6.1 months, and 60% of patients achieved minimal residual disease (MRD) negativity. The most common adverse events included pyrexia, neurological events, headache, febrile neutropenia, peripheral edema, nausea, hypokalemia, constipation, and anemia. CONCLUSIONS: Blinatumomab is a novel BiTE therapeutic monoclonal antibody that has shown promising results in patients with relapsed or refractory ALL or those achieving a CR with persistent MRD. Phase III clinical trials should define the optimal place in therapy of blinatumomab.

Prevention of stress ulceration: current trends in critical care.

OBJECTIVE: To identify the level of current intensivist's knowledge regarding risk assessment and intensive care unit (ICU) clinical practice pertaining to stress-related mucosal bleeding, including pharmacologic approaches for stress ulcer prevention. DESIGN: A nationwide survey of critical care physicians. STUDY POPULATION: Two thousand random physician members of the Society of Critical Care Medicine. MEASUREMENTS AND MAIN RESULTS: The response rate was 519 (26%) of 2000, with data analysis from 501 (25.1%) usable surveys. Respondents were affiliated with internal medicine (44.3%), surgery (42.3%), and anesthesiology (12.6%). Gut ischemia was indicated as the perceived major cause of stress ulceration (59.7%). The estimated incidence of clinically important bleeding was 2% or less by 62% of respondents; however, 28.6% of physicians surveyed initiate stress ulcer prophylaxis in all ICU patients, regardless of bleeding risk. Respiratory failure was most frequently indicated as a reason for stress ulcer prophylaxis (68.6%), followed by shock/hypotension (49.4%), sepsis (39.4%), and head injury/major neurologic insult (35.2%). The first-line agents selected for stress ulcer prophylaxis include histamine-2 receptor antagonists (63.9%), followed by proton pump inhibitors (23.1%), and sucralfate (12.2%). Concern for nosocomial pneumonia was regarded as more prevalent with antisecretory therapies in those who chose sucralfate (61%) as initial therapy compared with overall respondents (26.9%) (p < .001). CONCLUSIONS: The majority of intensivists surveyed recognize stress-related mucosal bleeding as a relatively infrequent event; however, implementation of a stress ulcer prophylaxis risk stratification scheme for ICU patients is necessary. Histamine-2 receptor antagonists are consistently perceived as appropriate initial agents, although proton pump inhibitors have become first-line therapy in an increasing percentage of critical care patients, despite limited data regarding their use in this population.