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Targeted oncology therapies have revolutionized cancer treatment over the last decade and have resulted in improved prognosis for many patients. This advance has emanated from elucidation of pathways responsible for tumorigenesis followed by targeting of these pathways by specific molecules. Cardiovascular care has become an increasingly critical aspect of patient care in part because patients live longer, but also due to potential associated toxicities from these therapies. Because of the targeted nature of cancer therapies, cardiac and vascular side effects may additionally provide insights into the basic biology of vascular disease. We herein provide the example of tyrosine kinase inhibitors utilized in chronic myelogenous leukemia to illustrate this medical transformation. We describe the vascular considerations for the clinical care of chronic myelogenous leukemia patients as well as the emerging literature on mechanisms of toxicities of the individual tyrosine kinase inhibitors. We additionally postulate that basic insights into toxicities of novel cancer therapies may serve as a new platform for investigation in vascular biology and a new translational research opportunity in vascular medicine.
Cardiovascular (CV) health has emerged as an important consideration in patients with chronic myeloid leukemia (CML) because of improved prognosis. Indeed, the success of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has increased the focus on survivorship and late toxicity in oncological care. Survivorship issues in this population include CV disease prevention, given its prevalence in the general population. The introduction of BCR-ABL1 TKIs represented a unique concept of indefinite cancer therapy, only recently evolving to include "treatment-free remission." Importantly, later-generation BCR-ABL1 TKIs have been associated with CV complications. Dasatinib has been associated with pleural/pericardial effusions and pulmonary hypertension, whereas nilotinib and ponatinib have been linked to the development of vascular occlusive events. There is currently a dearth of data with respect to the mechanisms of drug toxicities, the subsets of patients at risk, and prevention and treatment strategies to mitigate CV complications in patients with CML. Nevertheless, optimal patient CV risk assessment needs to become a more central tenet of patient care in CML. We propose several practical considerations for the practicing oncologist relative to the CV health of patients with CML, especially those on chronic TKI therapy.
© 2016 by The American Society of Hematology. All rights reserved.
For most patients with chronic myeloid leukemia, tyrosine kinase inhibitors (TKIs) have turned a fatal disease into a manageable chronic condition. Imatinib, the first BCR-ABL1 TKI granted regulatory approval, has been surpassed in terms of molecular responses by the second-generation TKIs nilotinib, dasatinib, and bosutinib. Recently, ponatinib was approved as the only TKI with activity against the T315I mutation. Although all TKIs are associated with nonhematologic adverse events (AEs), experience with imatinib suggested that toxicities are typically manageable and apparent early during drug development. Recent reports of cardiovascular AEs with nilotinib and particularly ponatinib and of pulmonary arterial hypertension with dasatinib have raised concerns about long-term sequelae of drugs that may be administered for decades. Here, we review what is currently known about the cardiovascular toxicities of BCR-ABL1 TKIs, discuss potential mechanisms underlying cardiovascular AEs, and elucidate discrepancies between the reporting of such AEs between oncology and cardiovascular trials. Whenever possible, we provide practical recommendations, but we concede that cause-directed interventions will require better mechanistic understanding. We suggest that chronic myeloid leukemia heralds a fundamental shift in oncology toward effective but mostly noncurative long-term therapies. Realizing the full potential of these treatments will require a proactive rational approach to minimize long-term cardiovascular and cardiometabolic toxicities.
© 2015 by American Society of Clinical Oncology.
BACKGROUND AIMS - To develop a treatment option for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) resistant to tyrosine kinase inhibitors (TKIs), we evaluated the anti-leukemic activity of T cells non-virally engineered to express a CD19-specific chimeric antigen receptor (CAR).
METHODS - A CD19.CAR gene was delivered into mononuclear cells from 10 mL of blood of healthy donors through the use of piggyBac-transposons and the 4-D Nucleofector System. Nucleofected cells were stimulated with CD3/CD28 antibodies, magnetically selected for the CD19.CAR, and cultured in interleukin-15-containing serum-free medium with autologous feeder cells for 21 days. To evaluate their cytotoxic potency, we co-cultured CAR T cells with seven Ph(+)ALL cell lines including three TKI-resistant (T315I-mutated) lines at an effector-to-target ratio of 1:5 or lower without cytokines.
RESULTS - We obtained ∼1.3 × 10(8) CAR T cells (CD4(+), 25.4%; CD8(+), 71.3%), co-expressing CD45RA and CCR7 up to ∼80%. After 7-day co-culture, CAR T cells eradicated all tumor cells at the 1:5 and 1:10 ratios and substantially reduced tumor cell numbers at the 1:50 ratio. Kinetic analysis revealed up to 37-fold proliferation of CAR T cells during a 20-day culture period in the presence of tumor cells. On exposure to tumor cells, CAR T cells transiently and reproducibly upregulated the expression of transgene as well as tumor necrosis factor-related apoptosis-inducing ligand and interleukin-2.
CONCLUSIONS - We generated a clinically relevant number of CAR T cells from 10 mL of blood through the use of piggyBac-transposons, a 4D-Nulcleofector, and serum/xeno/tumor cell/virus-free culture system. CAR T cells exhibited marked cytotoxicity against Ph(+)ALL regardless of T315I mutation. PiggyBac-mediated CD19-specific T-cell therapy may provide an effective, inexpensive and safe option for drug-resistant Ph(+)ALL.
Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.
The 2014 NCCN Clinical Practice Guidelines in Oncology for Chronic Myelogenous Leukemia recommend quantitative reverse-transcription polymerase chain reaction (QPCR) standardized to International Scale (IS) as the preferred method for monitoring molecular response to tyrosine kinase inhibitor (TKI) therapy. A BCR-ABL1 transcript level of 10% or less (IS) is now included as the response milestone at 3 and 6 months. Change of therapy to an alternate TKI is recommended for patients with BCR-ABL1 transcript levels greater than 10% (IS) at 3 months after primary treatment with imatinib. Continuing the same dose of TKI or switching to an alternate TKI are options for patients with BCR-ABL1 transcript levels greater than 10% (IS) at 3 months after primary treatment with dasatinib or nilotinib. The guidelines recommend 6-month evaluation with QPCR (IS) for patients with BCR-ABL1 transcript levels greater than 10% at 3 months. Monitoring with QPCR (IS) every 3 months is recommended for all patients, including those who meet response milestones at 3, 6, 12, and 18 months (BCR-ABL1 transcript level ≤10% [IS] at 3 and 6 months, complete cytogenetic response at 12 and 18 months).
OBJECTIVES - To distinguish chronic idiopathic neutrophilia (CIN) in a cost-effective manner from neutrophilia caused by important underlying illnesses.
METHODS - This was a retrospective review of patients visiting a Veterans Affairs Medical Center over the last 10 years with a diagnosis of leukocytosis or myeloproliferative disorder. Of this group, fifty-seven patients from 1999 to 2008 were identified with CIN. Clinical and laboratory parameters were examined to identify CIN and establish its course. Eighty-one patients who presented from 2005 to 2010 with myeloproliferative disorders were also studied at time of diagnosis to determine any possible confusion with CIN.
RESULTS - The patients with CIN were followed for a mean of ≥ 7.3 years without progression to other serious disorders. Compared to non-CIN patients evaluated for neutrophilia, in multiple logistic regression analyses, smoking (P = .001) and increased BMI (P = .004) were significantly associated with CIN. No CIN patient developed a clinically apparent myeloproliferative disorder other than chronic myeloid leukemia (CML). Of the patients with myeloproliferative neoplasms reviewed at the time of their initial diagnosis, only CML occasionally presented with a picture consistent with CIN. For nonsmokers, the BMI of CIN patients was significantly higher than the average VA population (P < .001).
CONCLUSION - Cigarette smoking and obesity are confirmed as factors associated with CIN and may be causative. CIN is unlikely to develop into a clinically recognizable myeloproliferative neoplasm other than CML. Cost-effective guidelines for the diagnostic evaluation of neutrophilia in otherwise healthy patients are presented.
BACKGROUND - Chronic myeloid leukemia (CML) is a myeloproliferative disorder with a unique genetic rearrangement, the Philadelphia chromosome. High reactive oxygen species (ROS) levels favor oxidative stress, which could play a vital role in normal processes and various pathophysiologies including neoplasm. Biomarkers of oxidative stress are measured as products of oxidized proteins and lipids. Plasma levels of protein carbonyl (PC), thiobarbituric acid reactive substances (TBARS) and total lipid hydroperoxide (LOOH) were used as biomarkers of oxidative stress in the past. The aim of this study was to evaluate the products of protein oxidation and lipid peroxidation in plasma as biomarkers of oxidative stress in CML patients.
PATIENTS AND METHODS - The study included 40 CML patients and 20 age- and sex-matched healthy volunteers. Of 40 CML patients, 28 were in chronic phase (CML-CP) and 12 in accelerated phase (CML-AP). Plasma levels of PC, TBARS and LOOH as biomarkers of oxidative stress were evaluated by spectrophotometric methods.
RESULTS - There were significant differences (P < .05) in plasma levels of PC, TBARS and LOOH in CML, CML-CP and CML-AP patients as compared to controls.
CONCLUSION - PC, TBARS and LOOH might reflect oxidative stress in CML patients and might be used as biomarkers in such patients.
Ehrlichiosis, a tickborne illness transmitted by tick vectors Amblyomma americanum and Ixodes scapularis, can be acquired in endemic areas. Clinical manifestations range from asymptomatic to fulminant in nature. We report three cases of ehrlichiosis in pediatric oncology patients, one of whom was a stem cell transplant recipient. Early symptoms included fever, malaise, and vague gastrointestinal symptoms. Laboratory abnormalities were initially attributed to chemotherapy toxicity. Illness was severe in all three patients and one patient died even after initiation of doxycycline. These cases emphasize the need for a high index of suspicion for tickborne illness in oncology patients, and the importance of a low threshold for starting empiric treatment before confirming the diagnosis.
Stem cells hold great promise as a means of treating otherwise incurable, degenerative diseases due to their ability both to self-renew and differentiate. However, stem cell damage can also play a role in the disease with the formation of solid tumors and leukaemias such as chronic myeloid leukaemia (CML), a hematopoietic stem cell (HSC) disorder. Despite recent medical advances, CML remains incurable by drug therapy. Understanding the mechanisms which govern chemoresistance of individual stem cell leukaemias may therefore require analysis at the single cell level. This task is not trivial using current technologies given that isolating HSCs is difficult, expensive, and inefficient due to low cell yield from patients. In addition, hematopoietic cells are largely non-adherent and thus difficult to study over time using conventional cell culture techniques. Hence, there is a need for new microfluidic platforms that allow the functional interrogation of hundreds of non-adherent single cells in parallel. We demonstrate the ability to perform assays, normally performed on the macroscopic scale, within the microfluidic platform using minimal reagents and low numbers of primary cells. We investigated normal and CML stem cell responses to the tyrosine kinase inhibitor, dasatinib, a drug approved for the treatment of CML. Dynamic, on-chip three-color cell viability assays revealed that differences in the responses of normal and CML stem/progenitor cells to dasatinib were observed even in the early phases of exposure, during which time normal cells exhibit a significantly elevated cell death rate, as compared to both controls and CML cells. Further studies show that dasatinib does, however, markedly reduce CML stem/progenitor cell migration in situ.