How I treat cardiovascular complications in patients with lymphoid malignancies.

The prognosis of several lymphoid malignancies has improved through development of novel therapies, combination with traditional chemotherapies, and delineation of appropriate therapeutic sequencing. Toxicities that are arising because of prolonged or multiple sequential therapeutic interventions are becoming increasingly impactful. Among the broad spectrum of complications that patients with lymphoid malignancies may experience, cardiovascular toxicities are significant in terms of morbidity and mortality. The entire cardiovascular system can be affected, but cardiomyopathy, heart failure, and arrhythmias remain of greatest concerns with the use of anthracyclines, hematopoietic stem cell transplantation, and radiation therapy in patients with lymphoid malignancies. These aspects will be covered in this article within the framework of case-based discussions. Key to the management of cardiovascular complications in patients with lymphoid malignancies is awareness and preparedness across the cancer continuum. Baseline risk stratification helps to direct surveillance and early intervention efforts before, during, and after cancer therapy, which are paramount for the best possible outcomes. Along these lines, the overall goal is to enable the best possible therapies for lymphoid malignancies without the complications of clinically significant cardiovascular events.

Evaluation of Burnout in a National Sample of Hematology-Oncology Pharmacists.

PURPOSE: To evaluate the prevalence of burnout among hematology-oncology pharmacists and factors associated with an increased risk of high burnout. METHODS: Between October and November 2020, members of the Hematology/Oncology Pharmacy Association were invited to complete an anonymous survey. Questions included the Maslach Burnout Inventory (MBI), Well-Being Index, and sociodemographic and occupational factors linked with burnout. RESULTS: Of 3,024 pharmacists contacted, 614 pharmacists (20.3%) responded to an online survey and 550 (18.2% of overall sample) completed the MBI and were included for analysis. Overall, high levels of burnout were observed in 61.8% of respondents based on the MBI, with 57.9% of respondents scoring high on the emotional exhaustion domain and 31.3% high in the depersonalization domain. Pharmacists with burnout worked on average 48.6 (±9.6) hours per week compared with 44.5 (±9.6) hours per week for those without high burnout and spent more time on administrative tasks per week (7.5 hours v 4.3 hours; all P < .001). Pharmacists reporting high burnout were more likely to report concern they had made a major medication error within the past 3 months (27.6% v 8.1%; P < .001) and greater intent to leave their current job within 2 years (60.3% v 19.0%; P < .001). CONCLUSION: Burnout is prevalent among hematology-oncology pharmacists and may affect both patient safety and the adequacy of the workforce. Risk factors for burnout among hematology-oncology pharmacists in this study may be targets for burnout mitigation and prevention strategies to reduce the impact on pharmacists and improve cancer care for patients.

Risk for Significant Kidney Function Decline After Acute Kidney Injury in Adults With Hematologic Malignancy.

INTRODUCTION: Acute kidney injury (AKI) affects 30% of adults hospitalized with hematologic malignancy. Little is known about the long-term impact on kidney outcomes in this population despite the close relationship between kidney function and malignancy treatment eligibility. The purpose of this population-based cohort study was to determine the effect of AKI on kidney function in the year following a new diagnosis of acute leukemia or lymphoma. METHODS: Participants were adults hospitalized within 3 weeks of malignancy diagnosis. Baseline kidney function was determined and AKI diagnosed using standardized criteria. Cox proportional hazard modeling examined the relationship between AKI and a ≥30% decline in estimated glomerular filtration rate (eGFR) from baseline in the 1 year following hospitalization as the primary endpoint. RESULTS: AKI occurred in 33% of 1064 participants, with 70% of episodes occurring within 48 hours of hospitalization, and significantly increased risk for a ≥ 30% decline in eGFR (hazard ratio [HR] 2.7, 95% confidence interval [CI] 2.2-3.5) and incident chronic kidney disease (HR 2.2, 95% CI 1.7-2.8). AKI remained a significant predictor of eGFR decline in subgroup and multivariable analyses (adjusted HR 1.9, 95% CI 1.4-2.7). A ≥ 30% decline in eGFR increased the risk for death within 1 year in participants with AKI (HR 2.1, 95% CI 1.3-3.3). CONCLUSION: Results aid in identifying individuals at highest risk for poor outcomes and highlight the need for research involving interventions that preserve kidney function from the time of initial hospitalization with a hematologic malignancy into the postdischarge period.

Treatment advances for pediatric and adult onset neoplasms with monocytosis.

PURPOSE OF REVIEW: For decades, the management of chronic myelomonocytic leukemia (CMML) or juvenile myelomonocytic leukemia (JMML) has been largely inextricable from myelodysplastic syndromes (MDS), myeloproliferative neoplasms, and acute myeloid leukemia. Hallmarks of these diseases have been the emergence of unique genomic signatures and discouraging responses to available therapies. Here, we will critically examine the current options for management and review the rapidly developing opportunities based on advances in CMML and JMML disease biology. RECENT FINDINGS: Few clinical trials have exclusively been done in CMML, and in JMML, the rarity of the disease limits wide scale participation. Recent case series in JMML suggest that hypomethylating agents (HMAs) are a viable option for bridging to curative intent with allogeneic hematopoietic stem cell transplant or as posttransplant maintenance. Emerging evidence has demonstrated targeting the RAS-pathway via MEK inhibition may also be considered. In CMML, treatment with HMAs is largely derived from data inclusive of MDS patients, including a small number of patients with dysplastic CMML variants. Based on CMML disease biology, additional therapeutic targets being investigated include inhibitors of splicing, CD123/dendritic cell axis, inherent GM-CSF progenitor cell hypersensitivity, and targeting the JAK/STAT pathway. Current evidence is also expanding for oral HMAs. The management of CMML and JMML is rapidly evolving and clinicians must be aware of the genetic landscape and expanding treatment options to ensure these rare populations are afforded therapeutic interventions best suited to their needs.

Analysis and impact of a multidisciplinary lymphoma virtual tumor board.

The aim is to prospectively evaluate the impact of a multidisciplinary lymphoma virtual tumor board. The utility of multi-site interactive lymphoma-specific tumor boards has not been reported. The Mayo Clinic Lymphoma Tumor Board is a component of the International Mayo Clinic Care Network (MCCN). The format includes the clinical case presentation, presentation of radiology and hematopathology findings by the appropriate subspecialist, proposed treatment options, review of the literature pertinent to the case, pharmacy contributions, and discussion followed by recommendations. Three hundred and nine consecutive highly selected real-time cases with a diagnosis of lymphoma were presented at the Mayo Clinic Lymphoma Tumor Board from January 2014 to June 2018 and decisions were prospectively tracked to assess its impact on the treatment decisions. A total of 309 cases were prospectively evaluated. One hundred and forty (45.3%) cases had some changes made or recommended. The total changes suggested were 179, as some cases had more than one recommendation. There were 93 (30%) clinical management recommendations, 45 (14.6%) additional testing recommendations, 29 (9.4%) pathology changes, and 6 (1.9%) radiology changes. In an electronic evaluation process, 93% of the responders reported an improvement in knowledge and competence, and 100% recommended no change in format of the board. A multidisciplinary lymphoma tumor board approach was found to have a meaningful impact on lymphoma patients while enhancing interdisciplinary interactions and education for multiple levels of the clinical care team.

A Prospective Survey of Outpatient Medication Adherence in Adult Allogeneic Hematopoietic Stem Cell Transplantation Patients.

Limited data exist regarding the prevalence and outcome of medication nonadherence in the adult allogeneic hematopoietic stem cell transplantation (allo-HSCT) population. The objective of this cross-sectional survey study is to determine the prevalence of medication nonadherence to immunosuppressant and nonimmunosuppressant medications in adult recipients of allo-HSCT. An electronic survey using previously validated medication adherence scales was distributed between December 2014 and April 2015 to 200 adult patients with at least 3 months of follow-up after allo-HSCT. Immunosuppressant serum drug levels and prescription refill records were retrospectively collected to assess correlation with survey responses. In the entire cohort, 51% of subjects (n = 102) reported nonadherence to nonimmunosuppressant medications (95% confidence interval [CI], 44.07% to 57.93%) on the Morisky Medication Adherence Scale. Of the 153 patients taking oral immunosuppressant medications at the time of the survey, 58 (37.9%) reported nonadherence to immunosuppressant therapy (95% CI, 30.22% to 45.6%), as measured by the Immunosuppressant Therapy Adherence Scale. Younger age and distress were associated with medication nonadherence. Nonadherence to immunosuppressant therapy was associated with mild chronic graft-vs-host disease (cGVHD), and a similar trend was observed for moderate cGVHD. Medication nonadherence was found to be highly prevalent for both immunosuppressant and nonimmunosuppressant medications in adult allo-HSCT recipient, and further study to identify interventions to improve adherence in these patients is warranted.

Myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes - Advances in treatment.

Optimal treatment for myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes remain to be defined and are currently extrapolated from MDS and MPN. The heterogeneity of these diseases and their rare occurrences add to this void. Supportive care therapies such as erythropoiesis stimulating agents, iron chelation and cytoreductive therapy do not have prospective evidence in these disorders and the only approved treatments, hypomethylating agents, are based on the inclusion of a small number of chronic myelomonocytic leukaemia patients in MDS predominant trials. While allogeneic stem cell transplant remains the only curative option, the median age at presentation (7th decade), comorbidities, risk of disease relapse, and transplant related morbidity and mortality, make this option accessible to < 10% of patients. The advent of next generation sequencing has better defined the genomic landscape and opened the doors for personalized medicine. Herein we focus on recent therapeutic advances and options in MDS/MPN overlap syndromes.

The impact of dose modification and temporary interruption of ibrutinib on outcomes of chronic lymphocytic leukemia patients in routine clinical practice.

To study the impact of dose modification and temporary interruption of ibrutinib in routine clinical practice, we conducted a retrospective study of consecutive CLL patients treated with ibrutinib outside the context of a clinical trial at Mayo Clinic, (Rochester, MN) from 11/2013 to 12/2017. Of 209 patients, 131 (74%) had unmutated IGHV, 38 (20%) had TP53 disruption, and 47 (22%) were previously untreated. A total of 87/209 (42%) patients started reduced dose ibrutinib (<420 mg daily; n = 43, physician preference; n = 33, concomitant medications; and n = 11, other). During 281 person-years of treatment, 91/209 patients had temporary dose interruption (54%, nonhematologic toxicity; 29%, surgical procedures; 10%, hematologic toxicity; and 7%, other). After a median follow-up of 24 months, the estimated median event-free survival (EFS) was 36 months, and median overall survival (OS) was not reached. On multivariable analyses, temporary ibrutinib interruption (hazard ratio [HR]: 2.37, P = .006) and TP53 disruption at ibrutinib initiation (HR: 1.81, P = .048) were associated with shorter EFS, whereas only TP53 disruption (HR: 2.38, P = .015) was associated with shorter OS. Initial ibrutinib dose and dose modification during therapy did not appear to impact EFS or OS. These findings illustrate the challenges associated with continuous oral therapy with ibrutinib in patients with CLL.

Impact of early rasburicase on incidence of clinical tumor lysis syndrome in lymphoma.

Early administration of rasburicase to enhance uric acid (UA) elimination has been adopted without robust evidence in support of its impact on clinical outcomes in tumor lysis syndrome (TLS), specifically, the prevention of acute kidney injury (AKI). This was a retrospective cohort study of adult lymphoma patients at intermediate or high risk for TLS. Excluded patients had AKI or were on dialysis at hospital admission. The incidence of new AKI in the setting of TLS was described along with predictors of its development, including early rasburicase use. In 383 included patients, the incidence of new-onset AKI during hospitalization was 6%. Predictors included age, history of renal or cardiovascular disease, and UA >8 mg/dL. Rasburicase use did not significantly impact the risk of developing AKI (HR 2.3; p = .11). The UA level at the time of administration did not modify the effect of rasburicase on prevention of AKI (p = .36 for the interaction term).

Common Adverse Effects of Novel Therapies for Multiple Myeloma (MM) and Their Management Strategies.

PURPOSE OF REVIEW: The purpose of this review was to evaluate management strategies for common adverse effects of novel therapies in multiple myeloma (MM), including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, and a histone deacetylase inhibitor. RECENT FINDINGS: There are several adverse effects that occur across multiple classes of antimyeloma drugs, including rash, peripheral neuropathy, infusion reactions, and cardiotoxicity, but most can be managed without complete discontinuation of the agent or abandonment of the class. Additionally, several agents have critically important drug-drug interactions or dose-modification implications in hepatic or renal insufficiency that can be easily overlooked, and exacerbate adverse effects. As treatment of MM moves from fixed-duration traditional chemotherapy to novel agent-based regimens, commonly administered continuously until disease progression or intolerable toxicities, providers must adopt their management strategies for both acute and long-term adverse effects. Early and frequent monitoring for therapy-related complications, dose adjustments when needed, and timely treatment for toxicities are all important steps toward ensuring longevity of treatment from a limited array of therapeutic options that currently exist for a disease with a relapsing and remitting course.

Safety and feasibility of lower antithrombin replacement targets in adult patients with hematological malignancies receiving asparaginase therapy.

The optimal antithrombin(AT) activity parameters for replacement as thromboprophylaxis following asparaginase remains unclear. This single-center, retrospective study evaluated two sets of AT replacement thresholds and targets in adults receiving asparaginase-containing chemotherapy. AT supplementation adhered to institutional standards, which lowered the AT activity target from 100% to 80% in 6/2014. Ninety-two patients were evaluated. Cumulative thrombosis incidence was 16% at 6 months (95%CI:6.8-24.0, maximum follow-up 315 days) with similar incidence between the 80% and 100% target groups, 14% (2 of the 14) and 13% (10 of the 78), respectively, with a small non-Line-Related DVT incidence (3%). Most thrombotic events occurred during induction chemotherapy and demonstrated no associations with replacement target, cumulative days or cumulative area under AT activity target, number of asparaginase doses, or cumulative asparaginase dose. Median estimated AT replacement expenditure was $34,963USD (IQR $16,260USD to $79,319USD) per patient. Cost-effectiveness and optimization of AT replacement for thromboprophylaxis following asparaginase requires prospective evaluation.

Pharmacovigilance during ibrutinib therapy for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in routine clinical practice.

Due to Cytochrome P450 3A (CYP3A) metabolism, clinical trials of ibrutinib-treated chronic lymphocytic leukemia (CLL) patients prohibited concurrent medications metabolized by CYP3A. We evaluated concomitant medication use in 118 ibrutinib-treated CLL patients outside the context of clinical trials. Seventy-five (64%) patients were on medications that could increase ibrutinib toxicity and 4 (3%) were on drugs that could decrease ibrutinib efficacy. Nineteen (16%) patients were on concomitant CYP3A inhibitors (11 moderate, 8 strong), and 4 (3%) were on CYP3A inducers (two patients were on both CYP3A inhibitors and inducers). Although the ibrutinib starting dose was changed in 18 patients on CYP3A interacting medications, no difference in 18-month progression-free survival or rate of ibrutinib discontinuation was observed in patients who were not. In routine clinical practice, 2 of 3 CLL patients commencing ibrutinib are on a concomitant medication with potential to influence ibrutinib metabolism. Formal medication review by a pharmacist should be considered in all patients initiating ibrutinib.

Correlation of Pain and Fluoride Concentration in Allogeneic Hematopoietic Stem Cell Transplant Recipients on Voriconazole.

Supportive care guidelines recommend antimold prophylaxis in hematopoietic stem cell transplant (HSCT) recipients deemed to have high risk for invasive fungal infection, leading to long-term use of voriconazole after allogeneic HSCT in patients who remain immunocompromised. Voriconazole has been associated with periostitis, exostoses, and fluoride excess in patients after solid organ transplantation, HSCT, and leukemia therapy. The aims of this study were to describe the frequency and clinical presentation of patients presenting with pain and fluoride excess among allogeneic HSCT patients taking voriconazole, to identify when a plasma fluoride concentration was measured with respect to voriconazole initiation and onset of pain, and to describe the outcomes of patients with fluoride excess in the setting of HSCT. A retrospective review was conducted of all adult allogeneic HSCT patients receiving voriconazole at Mayo Clinic in Rochester, Minnesota, between January 1, 2009 and July 31, 2012. Of 242 patients included, 32 had plasma fluoride measured to explore the etiology of musculoskeletal pain. In 31 patients with fluoride measurement while on voriconazole, 29 (93.5%) had elevated levels. The median plasma fluoride was 11.1 µmol/L (range, 2.4 to 24.7). The median duration of voriconazole was 163 days (range, 2 to 1327). The median time to fluoride measurement was 128 days after voriconazole initiation (range, 28 to 692). At 1 year after the start of voriconazole after HSCT, 15.3% of patients had developed pain associated with voriconazole use and 35.7% developed pain while on voriconazole after 2 years. Of the patients with an elevated fluoride level, 22 discontinued voriconazole; pain resolved or improved in 15, stabilized in 3, and worsened in 4 patients. Ten patients continued voriconazole; pain resolved or improved in 7, was attributable to alternative causes in 2, and undefined in 1. Serum creatinine, estimated glomerular filtration rate, alkaline phosphatase, and voriconazole concentration did not predict for fluoride excess and associated pain. Periostitis due to fluoride excess is a common adverse effect of voriconazole that should be considered in patients presenting with pain and is often reversible after drug discontinuation. Alternative antifungal agents with a lower risk for fluoride excess should be considered in patients receiving voriconazole who develop fluoride excess and pain.

Chronic Myelomonocytic Leukemia: a Genetic and Clinical Update.

Chronic myelomonocytic leukemia (CMML) is a clonal stem cell disorder, characterized by peripheral blood monocytosis and overlapping features between myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs). Clonal cytogenetic changes are seen in up to 30 % patients, while approximately 90 % have detectable molecular abnormalities. Most patients are diagnosed in the seventh decade of life. Gene mutations in ten-eleven translocation (TET) oncogene family member 2 (TET2) (60 %), SRSF2 (50 %), ASXL1 (40 %), and RAS (20-30 %) are frequent, with only frame shift and nonsense ASXL1 mutations negatively impacting overall survival. With the lack of formal guidelines, management and response criteria are often extrapolated from MDS and MPN. Contemporary molecularly integrated CMML-specific prognostic models include the Groupe Francais des Myelodysplasies (GFM) model and the Molecular Mayo Model, both incorporating ASXL1 mutational status. Hypomethylating agents and allogeneic stem cell transplant remain the two most commonly used treatment strategies, with suboptimal results. Clinical trials exploiting epigenetic and signal pathway abnormalities, frequent in CMML, offer hope and promise.

Antineoplastic agents and the associated myelosuppressive effects: a review.

Bone marrow is a complex organ responsible for the regulation of hematopoietic cell distribution throughout the human body. Patients receiving antineoplastic agents as a therapeutic intervention for hematologic malignancy often experience varying degrees of myelotoxicity. Antineoplastic agents cause hypocellularity in marrow resulting in a reduction in hematopoietic tissue activity and a corresponding decline in cell production. Quantifying the adverse effects on hematopoiesis is based on the properties of a single agent, the use of individual drugs within a combination chemotherapy regimen, and the course, or courses, of chemotherapy designed to treat cancer. The direct or indirect suppression of erythrocytes, granulocytes, and megakaryocytes has potential for multiple negative clinical consequences ranging from increased monitoring of blood counts to life-threatening infection and death. This review will provide an overview of the structure and function of competent adult bone marrow, describe the process of hematopoiesis, and characterize the myelotoxicities associated with common antineoplastic agents currently used in the treatment of cancer.