Returning to Work Following Hematopoietic Cell Transplantation: The Survivor's Perspective.

While curing a patient's underlying disease is the primary goal of physicians performing hematopoietic cell transplantation (HCT), the ultimate objective is to provide patients with optimal post-HCT quality of life. For many survivors, this includes returning to work (RTW). We conducted a survey of 1- to 5-yr post-HCT survivors at our center to evaluate their perspective on facilitators and barriers to RTW as well as to gauge interest in potentially useful RTW support interventions. Survivors aged 18 to 65 yrs (n = 994) were sent an annual survey that included 36 supplementary questions about post-HCT RTW. Survey questions were selected from published national cancer survivor surveys and then modified specifically for HCT survivors. Three hundred forty-four (35%) survivors with a mean age of 53 yrs completed the survey, of whom 272 (79%) had worked prior to their diagnosis. Of those 272 patients, 145 (53%) were working currently and another 22 (8%) had attempted to go back to work following HCT but were not presently working. We found that having had an allogeneic versus autologous HCT (P = .006) was associated with a decreased likelihood of currently working, whereas frequent employer communication (>once a month) (P = .070) and having a more supportive employer (P = .036) were associated with a greater chance of currently working. Of survivors currently working, 45% reported that they had made one or more changes to their work schedule (e.g., flexible schedule or part-time work) or environment (e.g., work from home) upon RTW. Ninety-five percent of responders reported that they could have benefited from RTW support provided by the transplant center, but only 13% indicated that they had received it. Education on RTW challenges, information on disability benefits, and access to physical therapy were among the most requested support interventions. To improve post-HCT quality of life for survivors open to assistance, providers should address work status and goals, recognize barriers to successful return, and offer RTW support including working directly with employers. Allogeneic HCT survivors are particularly vulnerable to failing attempts to RTW and should be the target of retention interventions. A previously published manuscript on RTW guidance for providers of stem cell transplant patients endorsed by the American Society of Transplant and Cellular Therapy is available in Open Access and can be used as a tool to counsel and support these patients.

Real-world evidence of heparin and citrate use in extracorporeal photopheresis: A hypothesis-generating data review of device settings and performance.

Extracorporeal photopheresis (ECP) is widely used for the treatment of cutaneous T-cell lymphoma, graft-vs-host disease, and other immune-related conditions. To avoid clotting during treatment, the ECP system used must be effectively primed with an anticoagulant. Heparin is the recommended anticoagulant for the THERAKOS CELLEX System, but acid citrate dextrose-A (ACDA) is often used. We compared system performance between these two anticoagulants for this ECP system. Deidentified data for ECP device performance were obtained at each treatment session, from automatically logged Smart Cards or labels completed by device operators. We compared the effects of ACDA or heparin on overall treatment duration, buffy coat (leukocyte) collection time, photoactivation time and the number of alarms and warnings. The variability in these parameters was also assessed. Data from 23 334 treat sessions were analyzed; ACDA was used in 34.4% and heparin in 65.6%. Overall, the ECP procedure duration, buffy coat collection time and photoactivation time were numerically similar regardless of whether ACDA or heparin was used, and regardless of needle mode. Photoactivation time variability was lower with ACDA compared with heparin in all needle modes. Among treatments that were completed automatically without any operator intervention, total treatment duration and photoactivation time were significantly reduced with ACDA use in both the double- and single-needle modes. The data presented indicate that, in both double- and single-needle modes, the THERAKOS® CELLEX® integrated ECP system performed similarly with ACDA compared to heparin, although ACDA demonstrated potential benefits in reducing variability in photoactivation time.

Cryopreservation of Growth Factor-Mobilized Peripheral Blood Stem Cells Does Not Compromise Major Outcomes after Allogeneic Hematopoietic Cell Transplantation: A Single-Center Experience.

During the Coronavirus disease 2019 pandemic, cryopreservation of allogeneic donor stem cell products ensured the availability of products at the start of conditioning for hematopoietic cell transplantation (HCT). Following recommendations from unrelated donor registries, including the National Marrow Donor Program, many centers began to cryopreserve related donor peripheral blood stem cell (PBSC) products. Throughout this process, several centers have published outcomes with cryopreserved versus fresh products, some with conflicting results. Even though cryopreservation was initially considered only a temporary measure driven by the pandemic, potential advantages include greater flexibility of transplantation timing. However, concerns about detrimental effects of cryopreservation, including increased risk of graft rejection, relapse, and consequent mortality, remained. The primary objective of the present study was to describe our center's experience comparing outcomes following PBSC transplantation with cryopreserved versus fresh grafts. This was an observational case study with a retrospective review comparing cryopreserved grafts (n = 213) to a recent historical cohort (controls) using fresh grafts (n = 167). In multivariable analyses, the adjusted hazard ratio (HR) for fresh versus cryopreserved grafts was 1.20 (95% confidence interval [CI], .79 to 1.82; P = .40) for overall mortality, .99 (95% CI, .55 to 1.77; P = .98) for nonrelapse mortality, and .94 (95% CI, .60 to 1.48; P = .80) for relapse. The adjusted HR for platelet engraftment was 1.31 (95% CI, 1.05 to 1.63; P = .02) and the odds ratio of grade III-IV acute GVHD was 1.75 (95% CI, 1.01 to 3.04; P = .05) with fresh grafts compared to cryopreserved grafts. There was no demonstrable difference in the risk of chronic GHVD. Although longer-term follow-up is needed, these data provide preliminary reassurance that in the event of another pandemic or should the logistical need arise in individual patients, cryopreservation of PBSC products is a reasonably safe alternative.

Bortezomib and Vorinostat Therapy as Maintenance Therapy Post Autologous Transplant for Non-Hodgkin's Lymphoma Using R-BEAM or BEAM Transplant Conditioning Regimen.

INTRODUCTION: The success of autologous stem cell transplantation (ASCT) for treating non-Hodgkin's lymphoma (NHL) is limited by its high relapse rates. To reduce the risk of relapse, additional maintenance therapy can be added post-transplant. In a non-transplant setting at the time of initiation of this study, both bortezomib and vorinostat had been studied alone or in combination for some NHL histology and showed some clinical activity. At our center, this combination therapy post-transplant for Multiple Myeloma (MM) showed acceptable toxicity. Therefore, it seemed reasonable to study this combination therapy post-ASCT for NHL. METHODS: NHL patients underwent conditioning for ASCT with rituximab, carmustine, etoposide, cytarabine, melphalan (R-BEAM)/carmustine, etoposide, cytarabine, melphalan (BEAM). After recovery from the acute transplant-related toxicity, combination therapy with IV bortezomib and oral vorinostat (BV) was started and was given for a total of 12 (28-day) cycles. RESULTS: Nineteen patients received BV post ASCT. The most common toxicities were hematologic, gastrointestinal, metabolic, fatigue and peripheral neuropathy. With a median follow-up of 10.3 years, 11 patients (58%) are alive without disease progression and 12 patients (63%) are alive. CONCLUSIONS: BV can be given post-ASCT for NHL and produces excellent disease-free and overall survival rates.

Fatigue in Hematopoietic Cell Transplantation Survivors: Correlates, Care Team Communication, and Patient-Identified Mitigation Strategies.

With improved survival after hematopoietic cell transplantation (HCT), the number of individuals at risk for persistent or late effects is increasing. The importance of optimizing HCT survivor health and well-being is mounting. Fatigue is a common post-transplantation symptom that impairs quality of life, yet it remains poorly understood and inadequately addressed. Multiple challenges to addressing fatigue exist, including its multidimensional presentation, multiple (often concomitant) causes, patient-clinician communication barriers, and few highly effective, evidence-based interventions that can be readily implemented. To address these challenges, we sought to better describe the impact and potential causes of fatigue in the post-transplantation setting, fatigue-related communication with clinicians, and the most effective patient-identified mitigation strategies (PIMS) for fatigue. A total of 1703 adult HCT recipients from a single center completed a survey including the Medical Outcomes Survey Short Form-36 (SF-36), PROMIS Fatigue, and other fatigue-related items between July 2017-June 2018. The survey was offered to recipients at their post-transplantation anniversary occurring during this interval. Two independent raters categorized free-text responses about fatigue PIMS. PROMIS Fatigue scores were dichotomized into low (≤55) or high (>55). Associations between high fatigue and participant characteristics and health outcomes were evaluated using the Fisher exact test for categorical variables and the Student 2-sample t test for continuous variables. Among the 1660 respondents with evaluable fatigue scores, 67% underwent allogeneic HCT. The majority of these (n = 1588; 96%) had a malignancy, with hematologic malignancy the most common diagnostic category (n = 1555; 94%). The median time post-transplantation was 11 years (interquartile range, 4 to 20 years). PROMIS item responses indicate that 44% of patients were at least somewhat fatigued and 37% were at least somewhat bothered by it. The mean fatigue score was 50.2 ± 11; 591 patients (36%) had high fatigue, which was associated with worse SF-36 scores across all domains (General Health, Physical Functioning, Emotional Well-being/Mental Health, Social Functioning, Role Limitation due to Physical Health, Role Limitation due to Emotional Health, Vitality [eg, energy], and Bodily Pain). High fatigue also was associated with self-reported chronic graft-versus-host disease, anxiety, depression and sleep problems. Diagnosis of plasma cell disorder and receipt of an autologous transplant were associated with high fatigue (P = .001). Among the 553 individuals who received an autologous transplant, 226 (41%) had multiple myeloma. Compared with the autologous transplant recipients without myeloma group, those with multiple myeloma were significantly more likely to have high fatigue (109 of 226 [48%] versus 118 of 325 [36%]; P < .01). Twenty percent of the patients with high fatigue did not discuss it with their care team. Among the 89 different reasons provided for not discussing it, the most common was "thought they already knew the answer" (n = 21). The 370 survivors with high fatigue who identified at least 1 most effective PIMS generated a total of 639 PIMS. Although the PIMS for fatigue spanned a wide array of strategies, most PIMS were related to sleep/rest (n = 192; 30%) or exercise (n = 139; 22%). Although fatigue is associated with worse HCT survivor-reported outcomes, it is only sometimes discussed with care teams. Survivors identify specific strategies that are most effective. Given its prevalence and impact, clinicians should promote communication about fatigue, treat underlying causes, and recommend sleep/rest and exercise, recognizing that individualized approaches also may be beneficial.

Late Effects of Severe Acute Graft-versus-Host Disease on Quality of Life, Medical Comorbidities, and Survival.

Grade III-IV acute graft-versus-host disease (aGVHD) is associated with high short-term morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). The long-term effects after recovery from grade III-IV aGVHD are unknown. This study aimed to analyze late medical comorbidities, quality of life, nonrelapse mortality, and survival in patients treated for grade III-IV aGVHD. Chart review identified late effects, and patients were asked to complete annual surveys to collect patient-reported outcomes. Outcomes were compared between patients with grade 0-I aGVHD and grade III-IV aGVHD who underwent HCT between 2001 and 2019 and survived for at least 1 year post-transplantation. Patients with a history of grade III-IV aGVHD (n = 192) had significantly higher rates of late medical comorbidities (P < .001) and worse physical (P = .01) and mental (P = .04) functioning compared with patients with grade 0-I aGVHD (n = 615). Patients who survived for >1 year post-transplantation and had prior grade III-IV aGVHD also had worse 5-year overall survival (77.5% versus 83.6%; P = .006) and higher nonrelapse mortality (19.2% versus 10.6%; P < .001) compared with those with a history of grade 0-I aGVHD. No between-group difference was found in cumulative incidence of chronic GVHD. Patients who recover from severe aGVHD remain vulnerable to developing late comorbidities. These patients would likely benefit from continued monitoring and supportive care in an attempt to prevent late effects and improve survival.

Successful Mobilization of Autologous Hematopoietic Peripheral Blood Stem Cells after Salvage Chemotherapy in Patients with Low CD34 Blood Cell Counts.

A major barrier for proceeding to autologous stem cell transplantation (ASCT) is an inability to mobilize and collect an adequate number of peripheral blood (PB) stem cells (PBSC) for the transplant graft. Plerixafor added to granulocyte colony stimulating factor (G-CSF) alone, without prior chemotherapy, significantly improves the mobilization of autologous PBSC in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). However, the efficacy of plerixafor and the best timing to give the drug to poorly mobilizing patients with very low PB CD34+ cell counts after salvage chemotherapy and G-CSF are not well defined. We hypothesized that PBSC mobilization and collection might be improved in heavily treated patients who mobilized very poorly after salvage chemotherapy and G-CSF by alternating the days of plerixafor administration and leukapheresis. A day of rest between plerixafor doses, while continuing G-CSF, could allow time for some replenishment of the marrow stem/progenitor cell pool before the next mobilization. A retrospective review of collection results in poorly mobilizing patients at our center was undertaken. Three cohorts were identified: those who got every-other-day plerixafor and leukapheresis, those who got sequential plerixafor and leukapheresis and those who got risk adapted plerixafor. Overall, 69% of patients with NHL and MM with PB CD34+ cell counts <5/µL after salvage chemotherapy and G-CSF were ultimately able to collect adequate CD34+ cells to support ASCT using daily plerixafor and leukapheresis. On the alternating plerixafor and leukapheresis schedule, all 17 patients achieved the cumulative CD34+ cell product goals required for ASCT. This positive observation after salvage chemotherapy and G-CSF led to the incorporation at our center of an alternate-day schedule of plerixafor and leukapheresis into our real-time risk adapted strategy for poor mobilizers. © 2023 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Neuropathy and Muscle Cramps in Autologous and Allogeneic Hematopoietic Cell Transplantation Survivors.

Although autologous and allogeneic hematopoietic cell transplantation are used to treat hematologic diseases, they are associated with high morbidity and mortality. The goal of this cross-sectional study was to describe the incidence, characteristics, severity and clinical correlates of neuropathy and muscle cramps, as self-reported by hematopoietic cell transplantation survivors. We included all respondents to a survey conducted July 1, 2020, to June 30, 2021. Surveys were completed online or on-paper according to participants' preferences; they received one reminder if no survey was received 1 month after distribution. Statistics are primarily descriptive comparing subgroups of patients. Of 4641 potentially eligible patients, 1745 responded and are included in the analysis. Participants (615 [35%] autologous, 1130 [65%] allogeneic) were a median age of 64.1 years (interquartile range [IQR] 55.2-70.8) and surveyed at a median of 11 years (IQR 4-21) after their most recent transplantation. Neuropathy symptoms were reported by 65% of autologous recipients, 66% of allogeneic transplant recipients with current chronic graft versus host disease (GVHD), and 45% of allogeneic recipients who never developed chronic GVHD. Muscle cramps were reported by 56% of autologous recipients, and 52% of allogeneic recipients and were rated as "very painful" by nearly half of patients who experienced them. These results suggest that neuropathy symptoms and muscle cramps are much more prevalent among survivors after hematopoietic cell transplantation than previously recognized. Better approaches for prevention and treatment of these bothersome complications are needed.

Long-term patient-reported neurocognitive outcomes in adult survivors of hematopoietic cell transplant.

Survivors of hematopoietic cell transplant (HCT) are at risk for neurocognitive impairments, which can negatively affect quality of life. Given limited studies, we aimed to describe the neurocognitive outcomes in a cohort of long-term adult HCT survivors. Eligible survivors (age ≥21 years at HCT and alive ≥2 years following HCT) completed a 60-question survey of neurocognitive function and quality of life, which included the Neuro-Quality of Life Cognitive Function Short Form (Neuro-QoL) and the Childhood Cancer Survivor Study Neurocognitive Questionnaire (NCQ). Analyses of risk factors included univariate comparisons and multivariable logistic regression. Survivors (n = 1861, 47.7% female, 65.6% allogeneic HCT) were surveyed at a median age of 64.2 years (interquartile range [IQR], 56.8-70.5) and a median 12.0 years (IQR, 6.0-21.0) from HCT. Survivors reported average Neuro-QoL scores (50.0 allogeneic; 49.2 autologous survivors) compared with an expected mean of 50 in the general population. On the NCQ, 17.4% to 31.2% of survivors reported impairments (Z-score >1.28) in task efficiency, memory, emotional regulation, or organization, compared with an expected 10% in the general population (all P < .01). In multivariable regression analyses, impaired Neuro-QoL (T-score <40) was independently associated with hearing issues (odds ratio [OR], 2.13; 95% confidence interval [CI], 1.46-3.10) and sleep impairment (OR, 4.41; 95% CI, 2.80-6.94) among allogeneic survivors, with comparable associations in autologous survivors. Overall, long-term adult HCT survivors reported average cognitive quality of life compared with the general population. Subsets of survivors with hearing issues and sleep impairments were more likely to report lower quality of life and impaired neurocognitive function, which may facilitate targeted monitoring or interventions following HCT.

Blood and marrow transplantation during the emerging COVID-19 pandemic: the Seattle approach.

On January 20, 2020, the first patient with coronavirus disease 2019 (COVID-19) in the United States of America was diagnosed in Washington state, which subsequently experienced rapidly increasing numbers of COVID-19 cases, hospitalizations, and deaths. This placed the Seattle Blood and Marrow Transplant Program at Fred Hutchinson Cancer Research Center (Fred Hutch) in the national epicenter of this pandemic. Here, we summarize the experience gained during our rapid response to the COVID-19 pandemic. Our efforts were aimed at safely performing urgent and potentially life-saving stem cell transplants in the setting of pandemic-related stresses on healthcare resources and shelter-in-place public health measures. We describe the unique circumstances and challenges encountered, the current state of the program amidst evolving COVID-19 cases in our community, and the guiding principles for recovery. We also estimate the collateral impact of directing clinical resources toward COVID-19-related care on cancer patients in need of stem cell transplantation. Although our experience was influenced by specific regional and institutional factors, it may help inform how transplant programs respond to COVID-19 and future pandemics.

Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial.

Patients who develop steroid-refractory acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation have poor prognosis, highlighting an unmet therapeutic need. In this open-label phase 2 study (ClinicalTrials.gov identifier: NCT02953678), patients aged at least 12 years with grades II to IV steroid-refractory aGVHD were eligible to receive ruxolitinib orally, starting at 5 mg twice daily plus corticosteroids, until treatment failure, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) at day 28; the key secondary end point was duration of response (DOR) at 6 months. As of 2 July 2018, 71 patients received at least 1 dose of ruxolitinib. Forty-eight of those patients (67.6%) had grade III/IV aGVHD at enrollment. At day 28, 39 patients (54.9%; 95% confidence interval, 42.7%-66.8%) had an overall response, including 19 (26.8%) with complete responses. Best ORR at any time was 73.2% (complete response, 56.3%). Responses were observed across skin (61.1%), upper (45.5%) and lower (46.0%) gastrointestinal tract, and liver (26.7%). Median DOR was 345 days. Overall survival estimate at 6 months was 51.0%. At day 28, 24 (55.8%) of 43 patients receiving ruxolitinib and corticosteroids had a 50% or greater corticosteroid dose reduction from baseline. The most common treatment-emergent adverse events were anemia (64.8%), thrombocytopenia (62.0%), hypokalemia (49.3%), neutropenia (47.9%), and peripheral edema (45.1%). Ruxolitinib produced durable responses and encouraging survival compared with historical data in patients with steroid-refractory aGVHD who otherwise have dismal outcomes. The safety profile was consistent with expectations for ruxolitinib and this patient population.

Factors affecting lymphocyte collection efficiency for the manufacture of chimeric antigen receptor T cells in adults with B-cell malignancies.

BACKGROUND: The clinical and procedural parameters that affect the optimal collection of lymphocytes for the production of chimeric antigen receptor (CAR) T cells remain undefined but are increasingly important, as commercial products are now available. We evaluated determinants of low lymphocyte collection efficiency (CE) and the rate of successful CAR T-cell manufacture in middle-aged and older adults with advanced B-cell malignancies. STUDY DESIGNS AND METHODS: Mononuclear cell collections using two apheresis platforms (COBE Spectra and Spectra Optia, Terumo BCT) from patients participating in a CD19-directed CAR T-cell therapy trial were reviewed. Patient- and disease-specific factors, peripheral blood counts, apheresis parameters, and product cell counts were analyzed to determine effects on lymphocyte CE. RESULTS: Ninety-two apheresis events from patients with acute lymphocytic leukemia (ALL) (n = 28), chronic lymphocytic leukemia (n = 18), and non-Hodgkin lymphoma (n = 46) were available for analysis. Forty-one collections (45%) had a lymphocyte CE of <40%. On multivariable analysis, age (every 10-year increase, odds ratio [OR] = 1.51; p = 0.034), disease type (chronic lymphocytic leukemia vs. ALL, OR = 0.24; p = 0.052; non-Hodgkin lymphoma vs. ALL, OR = 0.20; p = 0.009) and precollection platelets (every 10 × 103 /µL increase, OR = 1.07; p = 0.005) were appreciably associated with a lymphocyte CE of <40%. No major apheresis complications occurred. CONCLUSIONS: Lymphocyte collection at our center was well tolerated and 100% successful in manufacturing CD19-directed CAR T cells from adult patients with B-cell malignancies despite low CE in some patients. A diagnosis of ALL, advancing age, and higher preapheresis platelet counts were observed to be associated with low CE.

Use of hydroxyethyl starch in leukocytapheresis procedures does not increase renal toxicity.

BACKGROUND: Hydroxyethyl starch (HES) is reportedly associated with an increased risk of renal failure and death when used for fluid resuscitation in critically ill patients. HES can be used during therapeutic leukocytapheresis (TL) procedures to enhance cell separation. The purpose of this study was to evaluate the occurrence of adverse events associated with HES during TL procedures. STUDY DESIGN AND METHODS: We performed a retrospective review of patients who underwent TL with and without HES in the period 2009 to 2013 at six academic medical institutions. RESULTS: A difference-in-difference regression analysis was used to estimate the mean change before and after TL in selected outcomes in the HES group relative to the average change in the non-HES group. Selected outcomes included serum creatinine, estimated glomerular filtration rate (eGFR), and white blood cell (WBC) count. A total of 195 patients who underwent 278 TL procedures were studied. We found no significant differences in serum creatinine levels and eGFR on Days 1 and 7 after TL procedure between patients who received and those who did not receive HES. The rate of adverse events and overall and early mortality were similar in both groups. Patients with acute myeloid leukemia who received HES had greater WBC reduction when HES was used. Additionally, patients who received HES had improvement in pulmonary leukostasis symptoms. CONCLUSION: HES, used at low doses during TL procedures, was not associated with adverse events previously ascribed to its use as a volume expander.

Guidelines on the Use of Therapeutic Apheresis in Clinical Practice-Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Seventh Special Issue.

The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating, and categorizing indications for the evidence-based use of therapeutic apheresis in human disease. Since the 2007 JCA Special Issue (Fourth Edition), the Committee has incorporated systematic review and evidence-based approaches in the grading and categorization of apheresis indications. This Seventh Edition of the JCA Special Issue continues to maintain this methodology and rigor to make recommendations on the use of apheresis in a wide variety of diseases/conditions. The JCA Seventh Edition, like its predecessor, has consistently applied the category and grading system definitions in the fact sheets. The general layout and concept of a fact sheet that was used since the fourth edition has largely been maintained in this edition. Each fact sheet succinctly summarizes the evidence for the use of therapeutic apheresis in a specific disease entity. The Seventh Edition discusses 87 fact sheets (14 new fact sheets since the Sixth Edition) for therapeutic apheresis diseases and medical conditions, with 179 indications, which are separately graded and categorized within the listed fact sheets. Several diseases that are Category IV which have been described in detail in previous editions and do not have significant new evidence since the last publication are summarized in a separate table. The Seventh Edition of the JCA Special Issue serves as a key resource that guides the utilization of therapeutic apheresis in the treatment of human disease. J. Clin. Apheresis 31:149-162, 2016. © 2016 Wiley Periodicals, Inc.

NHLBI state of the science symposium in therapeutic apheresis: Knowledge gaps and research opportunities in the area of hematology-oncology.

The National Heart Lung and Blood Institute (NHLBI) hosted a two-day state of the science symposium on therapeutic apheresis in Bethesda, MD on November 28th-29th, 2012. The purpose of the symposium was multifaceted, and included the following aims: (a) To discuss this state of research and key scientific questions in apheresis medicine; (b) To identify gaps in knowledge for relevant cardiovascular diseases, hematological and oncological diseases, infectious diseases and sepsis, renal diseases, and neurological diseases where there may be strong therapeutic rationale for the application of apheresis treatments; (c) To explore ways of coordinating therapeutic apheresis with other medical disciplines and treatment modalities; (d) To identify and prioritize the most important research questions to be answered in apheresis medicine; and (e) To offer NHLBI suggestions on how a structured research approach can be applied to the therapeutic apheresis research agenda in future years. The following document summarizes three such key proposals presented at the meeting for evaluating apheresis therapy for the treatment of pain in sickle cell disease, heparin induced thrombocytopenia, and leukostasis from acute myeloid leukemia. The challenges and limitations regarding apheresis therapy for each disease are discussed, and avenues for future investigation for each disease are outlined.

Therapeutic apheresis for patients with cancer.

BACKGROUND: Disease complications associated with certain malignancies may be mediated by cells or soluble molecules that traffic in the bloodstream. Because of this, therapeutic apheresis (TA) methodologies have been used to selectively remove or manipulate specific molecules, antibodies, or cellular elements to treat the underlying pathological process. For some disorders, TA is utilized as a rapid-acting and short-term adjunct to conventional chemotherapy or immunotherapy. For others, a series of scheduled treatments is recommended for optimal management. In all cases, the risks, benefits, and costs must be strongly considered. METHODS: The current literature and published guidelines were reviewed to summarize the use of TA in the management of certain complications of cancer. RESULTS: Although TA is relatively safe and useful as a first-line or salvage modality for some disorders, few prospective, randomized clinical trials exist and the majority of evidence is derived from observational studies. Expert-based, clinical practice guidelines have been developed to inform hematology/oncology professionals and apheresis physicians about the efficacy and limitations of TA for malignancy-related indications. CONCLUSIONS: Certain oncological conditions respond to TA and consensus guidelines are available to support clinical decision-making. However, well-designed, prospective intervention trials are needed to better define the role of TA for a variety of disorders.

P-glycoprotein is downregulated in KG1a-primitive leukemia cells by LDL cholesterol deprivation and by HMG-CoA reductase inhibitors.

OBJECTIVE: P-glycoprotein (pgp) is a membrane transporter encoded by the multidrug resistance (MDR1, ABCB1) gene. Pgp is a poor prognostic factor in elderly patients with acute myeloid leukemia (AML). In addition to its role in drug efflux, pgp has been implicated in cellular cholesterol homeostasis. We investigated the effects of exogenous cholesterol removal on pgp expression and function. METHODS: KG1a drug-naïve, primitive leukemia cells were cultured in serum-free medium with or without the addition of low-density lipoprotein (LDL) cholesterol. After 72 hours, pgp expression and function was assessed by flow cytometry and total cholesterol content of the KG1a cells was determined by the Amplex Red cholesterol assay. The addition of clinically available cholesterol-lowering agents, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors to KG1a cells was also assessed. RESULTS: There was a 39% (SEM = 8.3%; p = 0.03) decrease in pgp protein expression after 3 days of serum-free culture. The decrease was also observed at the message and functional levels. In the presence of low-density lipoprotein cholesterol, pgp expression was restored to 86% of the basal value. Addition of a HMG-CoA reductase inhibitor to KG1a cells resulted in an additional 26% (lovastatin, p = 0.03) and 16% (pravastatin, p = 0.05) reduction in pgp, respectively. Furthermore, toxicity of the pgp substrate drug daunorubicin was enhanced following lovastatin preculture (p = 0.04). CONCLUSION: LDL cholesterol contributes to pgp expression and chemoresistance in primitive leukemia cells. Use of HMG-CoA reductase inhibitors may be of clinical value in lowering pgp expression in AML.