Cardiotoxicity in Hematopoietic Stem Cell Transplant: Keeping the Beat.

INTRODUCTION: The number of hematopoietic stem cell transplants (HSCTs) performed in the United States and worldwide is increasing. Cardiac events have been well described in HSCT, and the incidence and type of cardiac events have not changed over recent decades. PATIENTS AND METHODS: This study adds to the body of evidence in describing the incidence and type of cardiac events experienced by an allogeneic and autologous HSCT population at a single institution from 2012 to 2017. RESULTS: Sixty-five (9.8%) patients experienced cardiac events, including atrial arrhythmia (N = 39), acute heart failure (N = 9), acute coronary syndrome (N = 7), and new onset hypertension (N = 9), with a few instances of bradycardia, ventricular arrhythmia, pericardial effusion, and pericarditis. Our multivariable regression analysis identified age (older), creatinine (higher), and history of coronary artery disease to significantly correlate with risk of cardiac event (P = .005, P = .039, and P = .038, respectively). A subgroup analysis of those patients experiencing a cardiac event found pre-transplant atrial dilation by trans-thoracic echocardiogram to correlate with increased risk of atrial arrhythmia (33.8% vs. 9.7%; P = .03). Patients developing a CE had an increased risk of death within 1 year (11% vs. 32%; P < .001). CONCLUSION: We review our results in context of other important HSCT cardiac studies to illuminate the most relevant factors of medical history, laboratory data, and cardiac measurements that will identify patients at higher risk, allowing for intervention to improve HSCT outcomes.

Infusion reactions are common after high-dose carmustine in BEAM chemotherapy and are not reduced by lengthening the time of administration.

PURPOSE: Carmustine (BCNU) is used in the conditioning regimens BEAM and CBV for autologous stem cell transplantation. Carmustine-related infusion reactions, while not described in the BEAM literature, occurred in 95 % of patients who received CBV. The most common symptoms include flushing, facial pain, headache, and hypotension. These reactions have been attributed to the absolute ethanol that is used in the reconstitution process or alternatively by a direct effect of carmustine. It is currently recommended that carmustine 300 mg/m2 be infused over at least 100 min (3-5 mg/m2/min). Prior to October 2014, carmustine infusions were given over 90 min but were changed to 120 min based on the above recommendation. We compared the two infusion rates in patients receiving BEAM to see if lengthening the infusion decreased the frequency of reactions. METHODS: Overall, 100 patients received BCNU as part of BEAM or Zevalin BEAM and were equally divided between 90 and 120 min infusion times. The primary outcome was the incidence of infusion-related reactions which were graded based on CTCAE 4.03 descriptions of flushing and infusion-related reactions. We also evaluated the impact of premedication as well as the efficacy of medications used to treat infusion reactions. RESULTS: Between the years 2013-2016, there were 50 patients who received BCNU over 90 min and 50 patients over 120 min. There were no significant differences observed for diagnosis, age and gender between the two groups. Twenty-eight (56 %) in the 90-min and 26 (52 %) in the 120-min infusion intervals developed a reaction (p = 0.6882). Of the patients that developed a reaction, 19 patients (67 %) in the 90-min and all 26 patients (100 %) in the 120-min infusion were given premedications predominately acetaminophen, in addition to dexamethasone. Among reacting patients, 57 % of the 90-min and 65 % of the 120-min groups received additional intervention (p = 0.53). CONCLUSION: Infusion reactions during high-dose BCNU are common and are not clearly reduced by modestly extending the duration of infusion or giving premedications.

Autologous Stem Cell Mobilization in the Age of Plerixafor.

BACKGROUND: Autologous stem cell transplantation remains important in the treatment of myeloma and relapsed lymphoma. Plerixafor has been shown to significantly enhance stem cell mobilization but is very expensive. PATIENTS AND METHODS: We evaluated plerixafor use in the 3-year period after its approval in December 2008. RESULTS: A total of 277 patients with myeloma and lymphoma had stem cell mobilization; 97.5% were successfully mobilized, including 41.5% who received plerixafor. Plerixafor was generally used for rescue after suboptimal granulocyte-colony stimulating factor (G-CSF) mobilization ("just in time") or for remobilization after an unsuccessful attempt with chemotherapy plus G-CSF. In addition, 10% of patients received planned G-CSF plus plerixafor because of high risk factors for inadequate collection. Rescue plerixafor was more effective in patients with myeloma than lymphoma as after 1 dose of plerixafor; 85% versus 55% collected a minimum number of stem cells (2 × 10E6 CD34 cells/kg) for 1 transplant and 51% versus 15% collected > 5 × 10E6 CD34 cells/kg. After transplantation, there were no significant differences in engraftment as a consequence of plerixafor use. Among all patients, there were less platelet transfusions in patients provided ≥ 3.5 × 10E6 CD34(+) cells/kg. CONCLUSION: With the judicious use of plerixafor, nearly all patients can collect enough stem cells to proceed to transplantation. Further studies, including hematologic tolerance to posttransplantation therapy, are required to determine the cost-effectiveness of using plerixafor to convert adequate to more optimal mobilizers.

Hematopoietic cell transplantation in 2020: summary of year 2 recommendations of the National Marrow Donor Program's System Capacity Initiative.

The National Marrow Donor Program, in partnership with the American Society for Blood and Marrow Transplantation, sponsored and organized a series of symposia to identify complex issues affecting the delivery of hematopoietic cell transplantation (HCT) and to collaboratively develop options for solutions. "Hematopoietic Cell Transplantation in 2020: A System Capacity Initiative" used a deliberative process model to engage professional organizations, experts, transplant centers, and stakeholders in a national collaborative effort. Year 2 efforts emphasized data analysis and identification of innovative ideas to increase HCT system efficiency, address future capacity requirements, and ensure adequate reimbursement for HCT programs to meet the projected need for HCT. This report highlights the deliberations and recommendations of Year 2 and the associated symposium held in September 2011.

Successful collection and engraftment of autologous peripheral blood progenitor cells in poorly mobilized patients receiving high-dose granulocyte colony-stimulating factor.

BACKGROUND: Granulocyte Colony-Stimulating Factor (G-CSF) alone or in conjunction with chemotherapy is commonly used to mobilize hematopoietic progenitor cells (HPC) into peripheral blood for progenitor cell harvest for autologous HPC transplantation. However, in up to 30% of patients, HPC are not effectively mobilized. In this study, we report the efficacy and safety profiles of a mobilization strategy using high-dose (up to 36 µg/kg) G-CSF in poorly mobilized patients. STUDY DESIGN AND METHODS: Retrospective medical record reviews were performed for 392 patients who underwent autologous peripheral blood progenitor cell collection. A total of 56 patients were given high-dose G-CSF due to very ineffective mobilization and 35 of these patients underwent autologous HPC transplantation. The efficacy of mobilization, apheresis collection, and infusion were reviewed and analyzed. RESULTS: More than 2.5 × 10(6) CD34/Kg were collected in 88% of patients (49 of 56) who were placed on high-dose G-CSF due to very ineffective mobilization. Of the 35 patients who underwent HPC transplantation using the progenitor cells that were mobilized with high-dose G-CSF due to very ineffective mobilization, all had rapid and complete neutrophil and platelet engraftment comparable with good mobilizers. CONCLUSION: We conclude that collection of HPC using hyperstimulation with G-CSF is an effective alternative approach for HPC harvest for poorly mobilized patients.

The National Marrow Donor Program's Symposium on Hematopoietic Cell Transplantation in 2020: a health care resource and infrastructure assessment.

Hematopoietic cell transplantation (HCT) is the only known curative therapy for many patients with life-threatening hematologic and oncologic diseases. It is estimated that the National Marrow Donor Program(®) (NMDP) will facilitate 10,000 transplants by 2015, double the current number. To better understand the existing personnel and center infrastructure for HCT in the country and to address system capacity challenges to the future growth of HCT, the NMDP convened a diverse group of stakeholders and thought leaders representing HCT physicians, physician assistants, nurse practitioners, nurses, pharmacists, other healthcare providers, HCT program directors, hospital administrators, payors, and professional organizations. Working groups were formed to identify: capacity issues because of shortages in human resources, structural constraints, and patient access barriers including diversity and healthcare disparity challenges; recommendations to address challenges; and stakeholders to engage. This report details the deliberations and recommendations of a national symposium, "Hematopoietic Cell Transplantation in 2020: A Health Care Resource and Infrastructure Assessment," held in September 2010.

Late afternoon dosing of plerixafor for stem cell mobilization: a practical solution.

BACKGROUND: Plerixafor was recently approved for stem cell mobilization in patients who have non-Hodgkin lymphoma or multiple myeloma. However, the use of late evening (10 PM) injections is inconvenient for patients and requires an after-hours infrastructure that may not be readily available. PATIENTS AND METHODS: Based on an earlier study showing prolonged mobilization of stem cells in patients given plerixafor plus granulocyte colony-stimulating factor (G-CSF), we administered plerixafor at 5 PM and performed apheresis approximately 15 hours later. Plerixafor was administered primarily to patients who either had failed previous mobilization or were at risk for poor mobilization because of previous therapy, especially lenalidomide in patients who had multiple myeloma. RESULTS: Of 48 patients, including 24 with myeloma and 24 with lymphoma, 47 had enough stem cells collected (> 2 × 10E6 CD34+ cells/kg) to proceed to transplant, including all 13 patients who had failed previous chemotherapy plus G-CSF mobilization and 18 patients treated with four cycles or more of lenalidomide. The day +1 post-plerixafor increment in circulating CD34+ cells was greatest in patients who had the highest preplerixafor CD34 count; however, in patients with preplerixafor CD34+ cell counts < 10/µL (and who typically mobilize poorly), 83% of patients had enough stem cells collected to proceed to transplant. CONCLUSION: This study suggests that plerixafor is effective when given 15 hours before apheresis, even in a population at high risk for mobilization failure. A proposed cost-effective use of plerixafor is to administer it to patients who are inadequately mobilized with G-CSF alone or for salvage in patients who fail previous mobilization with chemotherapy plus G-CSF.

Outpatient high-dose melphalan in multiple myeloma patients.

BACKGROUND: The brief period of neutropenia and limited nonmarrow toxicity after high-dose melphalan (HDM) provide a rationale for outpatient treatment. STUDY DESIGN AND METHODS: Our experience with HDM (140-200 mg/m(2)) in 90 consecutive transplant episodes was retrospectively reviewed. Most patients were treated in an outpatient setting. Patients without a primary care provider (PCP) were electively admitted before the anticipated onset of neutropenia. Ceftriaxone was added to ciprofloxacin at the onset of neutropenia. All febrile patients were admitted. RESULTS: The median time from peripheral blood progenitor cell infusion to onset of neutropenia was 5 days (range, 4-6 days), and the mean duration of neutropenia was 5 days (range, 4-7 days). Thirty-eight transplants (42%) were performed entirely in the outpatient setting. The mean duration of hospitalization was 2.2 days in patients not electively admitted. The use of ceftriaxone was associated with a decreased risk for fever (39% vs. 79%) and reduced duration of hospitalization (1.6 days vs. 4.5 days) for nonelectively admitted patients. There was no treatment-related mortality. CONCLUSION: Ambulatory therapy with HDM is safe and can be achieved in a general outpatient setting. The predictable time to neutropenia allows even poor candidates for outpatient therapy to be admitted electively on Day +4. The apparent beneficial effect of ceftriaxone needs to be confirmed in randomized trials.

Sequential high-dose alkylating therapy and stem cell support for high-risk stage III breast cancer.

Patients who receive neoadjuvant chemotherapy for locally advanced breast cancer and have four or more ipsilateral axillary lymph nodes involved at surgery are at high risk for recurrence, with a median time to relapse of 18 months. We offered such patients high-dose chemotherapy with stem cell rescue. Patients received cyclophosphamide or paclitaxel and granulocyte colony-stimulating factor (G-CSF) to mobilize stem cells. Melphalan 140 mg/m2 was then given with stem cell rescue. Twenty-four to 35 days later, thiotepa 900 mg/m2 was given with stem cell rescue. Patients with hormone receptor-positive tumors received tamoxifen. We treated 14 patients in this fashion from 1995 to 1998. The mean age was 46.7 years. The majority of cancers were stage IIIB (79%). Thirteen women underwent mastectomy after anthracycline-containing chemotherapy and 50% had more than seven positive lymph nodes. Hospitalization was principally for neutropenic fever. Other morbidities were pneumonitis, cardiomyopathy, and grade 3/4 white blood cell (WBC) toxicity. No patient died of a treatment-related complication. Seven of 14 relapsed at 10, 12, <15, 15, 17, 21, and 36 months, with median follow-up of 26.5 months. Time to relapse in this small series is only modestly improved over historical experience with standard-dose adjuvant chemotherapy. Alternative strategies for treating locally advanced breast cancer should be pursued.