Publications by authors named "Alexandra C Cheerva"

9 Publications

  • Page 1 of 1

Immune profile differences between chronic GVHD and late acute GVHD: results of the ABLE/PBMTC 1202 studies.

Blood 2020 04;135(15):1287-1298

CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada.

Human graft-versus-host disease (GVHD) biology beyond 3 months after hematopoietic stem cell transplantation (HSCT) is complex. The Applied Biomarker in Late Effects of Childhood Cancer study (ABLE/PBMTC1202, NCT02067832) evaluated the immune profiles in chronic GVHD (cGVHD) and late acute GVHD (L-aGVHD). Peripheral blood immune cell and plasma markers were analyzed at day 100 post-HSCT and correlated with GVHD diagnosed according to the National Institutes of Health consensus criteria (NIH-CC) for cGVHD. Of 302 children enrolled, 241 were evaluable as L-aGVHD, cGVHD, active L-aGVHD or cGVHD, and no cGVHD/L-aGVHD. Significant marker differences, adjusted for major clinical factors, were defined as meeting all 3 criteria: receiver-operating characteristic area under the curve ≥0.60, P ≤ .05, and effect ratio ≥1.3 or ≤0.75. Patients with only distinctive features but determined as cGVHD by the adjudication committee (non-NIH-CC) had immune profiles similar to NIH-CC. Both cGVHD and L-aGVHD had decreased transitional B cells and increased cytolytic natural killer (NK) cells. cGVHD had additional abnormalities, with increased activated T cells, naive helper T (Th) and cytotoxic T cells, loss of CD56bright regulatory NK cells, and increased ST2 and soluble CD13. Active L-aGVHD before day 114 had additional abnormalities in naive Th, naive regulatory T (Treg) cell populations, and cytokines, and active cGVHD had an increase in PD-1- and a decrease in PD-1+ memory Treg cells. Unsupervised analysis appeared to show a progression of immune abnormalities from no cGVHD/L-aGVHD to L-aGVHD, with the most complex pattern in cGVHD. Comprehensive immune profiling will allow us to better understand how to minimize L-aGVHD and cGVHD. Further confirmation in adult and pediatric cohorts is needed.
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http://dx.doi.org/10.1182/blood.2019003186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146024PMC
April 2020

Benefits and challenges with diagnosing chronic and late acute GVHD in children using the NIH consensus criteria.

Blood 2019 07 1;134(3):304-316. Epub 2019 May 1.

British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.

Chronic graft-versus-host disease (cGVHD) and late acute graft-versus-host disease (L-aGVHD) are understudied complications of allogeneic hematopoietic stem cell transplantation in children. The National Institutes of Health Consensus Criteria (NIH-CC) were designed to improve the diagnostic accuracy of cGVHD and to better classify graft-versus-host disease (GVHD) syndromes but have not been validated in patients <18 years of age. The objectives of this prospective multi-institution study were to determine: (1) whether the NIH-CC could be used to diagnose pediatric cGVHD and whether the criteria operationalize well in a multi-institution study; (2) the frequency of cGVHD and L-aGVHD in children using the NIH-CC; and (3) the clinical features and risk factors for cGVHD and L-aGVHD using the NIH-CC. Twenty-seven transplant centers enrolled 302 patients <18 years of age before conditioning and prospectively followed them for 1 year posttransplant for development of cGVHD. Centers justified their cGVHD diagnosis according to the NIH-CC using central review and a study adjudication committee. A total of 28.2% of reported cGVHD cases was reclassified, usually as L-aGVHD, following study committee review. Similar incidence of cGVHD and L-aGVHD was found (21% and 24.7%, respectively). The most common organs involved with diagnostic or distinctive manifestations of cGVHD in children include the mouth, skin, eyes, and lungs. Importantly, the 2014 NIH-CC for bronchiolitis obliterans syndrome perform poorly in children. Past acute GVHD and peripheral blood grafts are major risk factors for cGVHD and L-aGVHD, with recipients ≥12 years of age being at risk for cGVHD. Applying the NIH-CC in pediatrics is feasible and reliable; however, further refinement of the criteria specifically for children is needed.
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http://dx.doi.org/10.1182/blood.2019000216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911839PMC
July 2019

The safety and efficacy of clofarabine in combination with high-dose cytarabine and total body irradiation myeloablative conditioning and allogeneic stem cell transplantation in children, adolescents, and young adults (CAYA) with poor-risk acute leukemia.

Bone Marrow Transplant 2019 02 13;54(2):226-235. Epub 2018 Jun 13.

Departments of Pediatrics, Valhalla, NY, USA.

Acute leukemias in children with CR3, refractory relapse, or induction failure (IF) have a poor prognosis. Clofarabine has single agent activity in relapsed leukemia and synergy with cytarabine. We sought to determine the safety and overall survival in a Phase I/II trial of conditioning with clofarabine (doses 40 - 52 mg/m), cytarabine 1000 mg/m, and 1200 cGy TBI followed by alloSCT in children, adolescents, and young adults with poor-risk leukemia. Thirty-seven patients; Age 12 years (1-22 years); ALL/AML: 34:3 (18 IF, 10 CR3, 13 refractory relapse); 15 related, 22 unrelated donors. Probabilities of neutrophil, platelet engraftment, acute GvHD, and chronic GvHD were 94%, 84%, 49%, and 30%, respectively. Probability of day 100 TRM was 8.1%. 2-year EFS (event free survival) and OS (overall survival) were 38.6% (CI: 23-54%), and 41.3% (CI: 25-57%). Multivariate analysis demonstrated overt disease at time of transplant (relative risk (RR) 3.65, CI: 1.35-9.89, P = 0.011) and umbilical cord blood source (RR 2.17, CI: 1.33-4.15, P = 0.019) to be predictors of worse EFS/OS. This novel myeloablative conditioning regimen followed by alloSCT is safe and well tolerated in CAYA with very poor-risk ALL or AML. Further investigation in CAYA with better risk ALL and AML undergoing alloSCT is warranted.
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http://dx.doi.org/10.1038/s41409-018-0247-9DOI Listing
February 2019

Cytomegalovirus Treatment in Pediatric Hematopoietic Stem Cell Transplant Patients.

J Pediatr Hematol Oncol 2017 05;39(4):241-248

*Department of Pharmacy, Norton Children's Hospital ‡Pediatric Cancer and Blood Disorders, University of Louisville, Louisville, KY †Department of Pharmacy, Children's Hospital Colorado, Aurora, CO.

Cytomegalovirus (CMV) is a frequent complication of hematopoietic stem cell transplant in pediatric patients, with significant morbidity and mortality. Antiviral drugs are used as prophylactic, preemptive or therapeutic medicines; however, no uniform guidelines exist for the best strategy to prevent CMV disease. Resistance to standard antiviral therapies can lead to further difficulty in managing CMV disease. Studies for investigational therapies are underway and could provide options for treatment of resistant CMV, while limiting toxicities associated with currently used antiviral therapies.
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http://dx.doi.org/10.1097/MPH.0000000000000730DOI Listing
May 2017

A phase I trial combining decitabine/dendritic cell vaccine targeting MAGE-A1, MAGE-A3 and NY-ESO-1 for children with relapsed or therapy-refractory neuroblastoma and sarcoma.

Cancer Immunol Immunother 2015 Oct 24;64(10):1251-60. Epub 2015 Jun 24.

Department of Pediatrics, Hematology/Oncology, University of Louisville, 571 South Floyd Street, Suite 445, Louisville, KY, 40202, USA.

Antigen-specific immunotherapy was studied in a multi-institutional phase 1/2 study by combining decitabine (DAC) followed by an autologous dendritic cell (DC)/MAGE-A1, MAGE-A3 and NY-ESO-1 peptide vaccine in children with relapsed/refractory solid tumors. Patients aged 2.5-15 years with relapsed neuroblastoma, Ewing's sarcoma, osteosarcoma and rhabdomyosarcoma were eligible to receive DAC followed by DC pulsed with overlapping peptides derived from full-length MAGE-A1, MAGE-A3 and NY-ESO-1. The primary endpoints were to assess the feasibility and tolerability of this regimen. Each of four cycles consisted of week 1: DAC 10 mg/m(2)/day for 5 days and weeks 2 and 3: DC vaccine once weekly. Fifteen patients were enrolled in the study, of which 10 were evaluable. Generation of DC was highly feasible for all enrolled patients. The treatment regimen was generally well tolerated, with the major toxicity being DAC-related myelosuppression in 5/10 patients. Six of nine patients developed a response to MAGE-A1, MAGE-A3 or NY-ESO-1 peptides post-vaccine. Due to limitations in number of cells available for analysis, controls infected with a virus encoding relevant genes have not been performed. Objective responses were documented in 1/10 patients who had a complete response. Of the two patients who had no evidence of disease at the time of treatment, one remains disease-free 2 years post-therapy, while the other experienced a relapse 10 months post-therapy. The chemoimmunotherapy approach using DAC/DC-CT vaccine is feasible, well tolerated and results in antitumor activity in some patients. Future trials to maximize the likelihood of T cell responses post-vaccine are warranted.
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http://dx.doi.org/10.1007/s00262-015-1731-3DOI Listing
October 2015

Cerebral toxoplasmosis after tandem high-dose chemotherapy and autologous hematopoietic cell transplant for neuroblastoma.

J Pediatr Hematol Oncol 2013 Mar;35(2):e50-2

Department of Pediatrics, University of Louisville, Louisville, KY, USA.

Toxoplasmosis is a well-recognized life-threatening complication of hematopoietic cell transplantation (HCT). This report describes a pediatric patient with stage 4 neuroblastoma who developed cerebral toxoplasmosis after tandem high-dose chemotherapy with autologous HCT. Toxoplasmosis is rare in patients undergoing autologous HCT; however, tandem autologous HCT is more immunosuppressive than a single autologous HCT. Toxoplasmosis is a potential complication in autologous as well as allogeneic transplants, and should be considered in any post-HCT patient with neurological dysfunction. Rapid diagnosis and immediate antimicrobial treatment are crucial to avoid morbidity and mortality. Evaluation of toxoplasma serology should be standard in all patients undergoing tandem autologous HCT and seropositive patients should be started on appropriate prophylactic therapy.
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http://dx.doi.org/10.1097/MPH.0b013e3182677e84DOI Listing
March 2013

A pilot study of addition of amifostine to melphalan, carboplatin, etoposide, and cyclophosphamide with autologous hematopoietic stem cell transplantation in pediatric solid tumors-A pediatric blood and marrow transplant consortium study.

J Pediatr Hematol Oncol 2008 Mar;30(3):204-9

Department of Pediatrics, Section of Hematology/Oncology, New York Medical College, Valhalla, NY 10595, USA.

Limited information is available regarding the use of amifostine in pediatric hematopoietic stem cell transplant (HSCT) patients. Melphalan, carboplatin, etoposide +/- cyclophosphamide is a commonly used preparatory regimen in pediatric solid tumor HSCT. Therefore, we decided to determine the feasibility of the addition of amifostine (750 mg/m b.i.d. x 4 d) to melphalan (200 mg/m), carboplatin (1200 mg/m), and etoposide (800 mg/m) (level 1) and escalating doses of cyclophosphamide (3000 mg/m and 3800 mg/m, levels 2 and 3, respectively) followed by autologous HSCT. Thirty-two patients with a variety of pediatric solid tumors were studied. Seventeen patients were accrued at level 1, 9 at level 2, and 6 at level 3. Major toxicities during the administration of the preparatory regimen were hypocalcemia, emesis, and hypotension. Hypocalcemia required aggressive calcium supplementation during the conditioning phase. No dose limiting toxicities were encountered at level 3. Amifostine at 750 mg/m b.i.d. for 4 days can be administered with a double alkylator regimen consisting of melphalan (200 mg/m), cyclophosphamide (up to 3800 mg/m), carboplatin (1200 mg/m), and etoposide (800 mg/m) with manageable toxicities.
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http://dx.doi.org/10.1097/MPH.0b013e318162bd0cDOI Listing
March 2008

BK virus-associated hemorrhagic cystitis in pediatric cancer patients receiving high-dose cyclophosphamide.

J Pediatr Hematol Oncol 2007 Sep;29(9):617-21

Pediatric Hematology and Oncology, University of Louisville, and Kosair Children's Hospital, Louisville, KY 40202, USA.

Hemorrhagic cystitis (HC) is a known complication of oxazophosphorine chemotherapy. BK virus (BKV) has been commonly found to be associated with hematuria in stem cell transplant patients; however, it has rarely been reported after cyclophosphamide chemotherapy alone. The authors present 3 cases of BK viruria with HC in nontransplant pediatric oncology patients. The 3 patients with BKV had more prolonged hematuria (14 to 16 wk) compared with 1 patient with BKV-negative HC (10 wk). The HC necessitated chemotherapy delays and also prolonged supportive care. One patient was treated with intravenous cidofovir with resolution of BK viruria and hematuria. BKV may have an association with the development of HC in nonstem cell transplant patients receiving high-dose oxazophosphorine chemotherapy. HC may present early and be more prolonged in patients with BK viruria. Patients with HC after cyclophosphamide or ifosfamide with negative bacterial cultures should be studied for BKV. Cidofovir may be beneficial in certain patients with BK viruria and HC; however, definitive data will require a clinical trial.
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http://dx.doi.org/10.1097/MPH.0b013e3181461f6cDOI Listing
September 2007