Outcome and Prognostic Indicators of Patients with Hematopoietic Stem Cell Transplants Admitted to the Intensive Care Unit

The prognosis of patients with hematopoietic stem cell transplants (HSCTs) who require admission to the intensive care unit (ICU) has been regarded as extremely poor. We sought to re-evaluate recent outcomes and predictive factors in a retrospective cohort study. Among the 605 adult patients that received an HSCT between 2001 and 2006, 154 required admission to the ICU. Of these, 47% were discharged from the ICU, 36% were discharged from the hospital, and 19% survived 6 months. Allogeneic transplant, mechanical ventilation, vasopressor-use, and neutropenia were each associated with increased mortality, and the mortality of patients with all four characteristics was 100%. Hemodialysis was also associated with increased mortality in a Kaplan-Meier analysis but did not appear important in a multivariate tree analysis. A final Cox model confirmed that allogeneic transplant, mechanical ventilation, and vasopressor-use were each independent risk factors for mortality in the 6 months following ICU admission

Evaluation of 11C-Acetate and 18 F-FDG PET/CT in mouse multidrug resistance gene-2 deficient mouse model of hepatocellular carcinoma

Background Hepatocellular carcinoma (HCC) remains a global health problem with unique diagnostic and therapeutic challenges, including difficulties in identifying the highest risk patients. Previous work from our lab has established the murine multidrug resistance-2 mouse (MDR2) model of HCC as a reasonable preclinical model that parallels the changes seen in human inflammatory associated HCC. The purpose of this study is to evaluate modalities of PET/CT in MDR2−/− mice in order to facilitate therapeutic translational studies from bench to bedside. Methods 18F-FDG and 11C-acetate PET/CT was performed on 12 m MDR2−/− mice (n = 3/tracer) with HCC and 12 m MDR2−/+ control mice (n = 3/tracer) without HCC. To compare PET/CT to biological markers of HCC and cellular function, serum alpha-fetoprotein (AFP), lysophosphatidic acid (LPA), cAMP and hepatic tumor necrosis factor α (TNFα) were quantified in 3-12 m MDR2−/− (n = 10) mice using commercially available ELISA analysis. To translate results in mice to patients 11C-acetate PET/CT was also performed in 8 patents suspected of HCC recurrence following treatment and currently on the liver transplant wait list. Results Hepatic18F-FDG metabolism was not significantly increased in MDR2−/− mice. In contrast, hepatic 11C-acetate metabolism was significantly elevated in MDR2−/− mice when compared to MDR2−/+ controls. Serum AFP and LPA levels increased in MDR2−/− mice contemporaneous with the emergence of HCC. This was accompanied by a significant decrease in serum cAMP levels and an increase in hepatic TNFα. In patients suspected of HCC recurrence there were 5 true positives, 2 true negatives and 1 suspected false 11C-acetate negative. Conclusions Hepatic 11C-acetate PET/CT tracks well with HCC in MDR2−/− mice and patients with underlying liver disease. Consequently 11C-acetate PET/CT is well suited to study 1) HCC emergence/progression in patients and 2) reduce animal numbers required to study new chemotherapeutics in murine models of HCC

Minimal Residual Disease as a Predictive Factor for Relapse after Allogeneic Hematopoietic Stem Cell Transplant in Adult Patients with Acute Myeloid Leukemia in First and Second Complete Remission

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is potentially curative for patients with high-risk leukemia, but disease recurrence remains the leading cause of treatment failure. Our objective was to determine the impact of minimal residual disease (MRD) by any technique in adult patients with acute myeloid leukemia (AML) in morphologic first and second complete remission undergoing allo-SCT. Fifty nine patients were eligible for the study of 160 patients transplanted over ten years. For the MRD assessment we used multiparametric flow cytometry, cytogenetics and fluorescent in situ hybridization; 19 patients (32.2%) were identified as MRD positive. Patients with MRD had a consistently worse outcome over those without MRD, with 3-years leukemia-free survival (LFS) of 15.8% vs. 62.4% and overall survival (OS) of 17.5% vs. 62.3%. Relapse rate was significantly higher in MRD-positive patients; 3 years relapse rate in MRD-positive patients was 57.9% vs. 15.1% in MRD-negative patients. Detection of MRD in complete remission was associated with increased overall mortality (HR = 3.3; 95% CI: 1.45-7.57; p = 0.0044) and relapse (HR = 5.26; 95% CI: 2.0-14.0; p = 0.001), even after controlling for other risk factors. Our study showed that for patients in morphologic complete remission the presence of MRD predicts for significantly increased risk of relapse and reduced LFS and OS

Chronic Embolic Pulmonary Hypertension Caused by Pulmonary Embolism and Vascular Endothelial Growth Factor Inhibition

Our understanding of the pathophysiological basis of chronic thromboembolic pulmonary hypertension (CTEPH) will be accelerated by an animal model that replicates the phenotype of human CTEPH. Sprague-Dawley rats were administered a combination of a single dose each of plastic microspheres and vascular endothelial growth factor receptor antagonist in polystyrene microspheres (PE) + tyrosine kinase inhibitor SU5416 (SU) group. Shams received volume-matched saline; PE and SU groups received only microspheres or SU5416, respectively. PE + SU rats exhibited sustained pulmonary hypertension (62 ± 13 and 53 ± 14 mmHg at 3 and 6 weeks, respectively) with reduction of the ventriculoarterial coupling in vivo coincident with a large decrement in peak rate of oxygen consumption during aerobic exercise, respectively. PE + SU produced right ventricular hypokinesis, dilation, and hypertrophy observed on echocardiography, and 40% reduction in right ventricular contractile function in isolated perfused hearts. High-resolution computed tomographic pulmonary angiography and Ki-67 immunohistochemistry revealed abundant lung neovascularization and cellular proliferation in PE that was distinctly absent in the PE + SU group. We present a novel rodent model to reproduce much of the known phenotype of CTEPH, including the pivotal pathophysiological role of impaired vascular endothelial growth factor-dependent vascular remodeling. This model may reveal a better pathophysiological understanding of how PE transitions to CTEPH in human treatments

Marrow transplantation from unrelated donors for patients with severe aplastic anemia who have failed immunosuppressive therapy

AbstractAllogeneic marrow transplantation offers curative therapy for patients with aplastic anemia. We analyzed retrospective results in 141 patients with severe aplastic anemia who received transplants between 1988 and 1995 from an unrelated volunteer donor identified through the National Marrow Donor Program (NMDP). All patients had failed one or more courses of immunosuppressive therapy. Of the patients, 121 (86%) received a radiation-containing conditioning regimen, and 20 (14%) were given chemotherapy only. Based on serologic human leukocyte antigen (HLA) typing (class I and II), 105 patients (74%) received HLA-matched marrow, and 36 (26%) received marrow mismatched for at least one HLA-A, -B, or -DR antigen. Allele-level (molecular) typing for HLA-DRB1 was available in 108 donor-recipient pairs; 77 patients received DRB -matched and 31 DRB1-mismatched transplants. All but 13% of patients were given a cyclosporine-containing regimen for graft-vs.-host disease (GVHD) prophylaxis, and 45 patients (32%) received marrow that was T cell-depleted. Among 131 evaluable patients, 116 (89%) achieved sustained engraftment and 15 (11%) did not. Among patients with engraftment, acute GVHD of grades II-IV developed in 60 patients (52%) and extensive chronic GVHD in 24 patients at risk (31%). Currently, 51 patients (36%) are surviving at 11-94 months (median 36) after transplantation. All but five have Karnofsky scores > or =80. Patients who received a serologically matched transplant fared somewhat better than did patients given a serologically mismatched transplant p = 0.03). Patients with donors matched by both serology and allele-level DRB1 typing had significantly better survival than DRB1-mismatched patients with 56 vs. 15% surviving at 3 years p = 0.001). Outcome in patients transplanted within 3 years of diagnosis was superior to that among patients transplanted with greater delay. Major causes of death were graft failure, GVHD, and infections. These data suggest that unrelated marrow transplantation offers successful therapy for a proportion of patients who have failed immunosuppressive therapy.Biol Blood Marrow Transplant 1999;5(4):243-52

Marrow transplants from unrelated donors for patients with aplastic anemia: Minimum effective dose of total body irradiation

AbstractPatients with aplastic anemia who do not have suitably HLA-matched, related donors generally receive immunosuppressive treatment as first-line therapy and are considered for transplantation from an unrelated donor only if they fail to respond to immunosuppressive treatment. In this setting, rates of transplantation-related morbidity and mortality have been high. We conducted a prospective study to determine the minimal dose of total body irradiation (TBI) sufficient to achieve sustained engraftment when it is used in combination with 3 cycles of 30 mg/kg of antithymocyte globulin (ATG) and 4 cycles of 50 mg/kg of cyclophosphamide (CY). We also wanted to determine the tolerability and toxicity of the regimen. The starting dosage of TBI was 3 x 200 cGy given over 2 days following CY/ATG. The TBI dose was to be escalated in increments of 200 cGy if graft failure occurred in the absence of prohibitive toxicity, and de-escalated for toxicity in the absence of graft failure. Twenty-one female and 29 male patients aged 1.3 to 46.5 years (median age, 14.4 years) underwent transplantation at 14 medical centers. The time interval from diagnosis to transplantation was 2.8 to 264 months (median, 14.5 months). All patients had been transfused multiple times and all had received 1 to 11 courses (median, 4 courses) of immunosuppressive treatment and other modalities of treatment. In 38 cases, the donors were HLA-A, -B and -DR phenotypically matched with the patients, and, in 12 cases, the donor phenotype differed from that of the recipient by 1 HLA antigen. Recipients of mismatched transplants were considered separately for TBI dose modification, and this study is still ongoing. Seven patients did not tolerate ATG and were prepared with 6 x 200 cGy of TBI plus 120 mg/kg of CY. Of the HLA-matched recipients prepared with CY/ATG/TBI, all 20 who received 3 x 200 or 2 x 200 cGy of TBI achieved engraftment, and 10 are alive. Of the 13 patients who received 1 x 200 cGy of TBI, 1 failed to engraft, and 8 are alive. Each of 10 patients who received an HLA-nonidentical transplant achieved engraftment, and 3 of 6 who were given 3 x 200 cGy of TBI, and 4 of 4 who were given 2 x 200 cGy are alive. Pulmonary toxicity occurred in 8 of 30 patients who were given 3 x 200 or 2 x 200 cGy of TBI concurrently with ATG and CY at 200 mg/kg, and in 2 of 13 patients who received 1 x 200 cGy of TBI, a pattern that suggests a decrease in toxicity with TBI dose de-escalation. Overall, the highest probability of survival (73%) was observed among patients who underwent transplantation within 1 year of diagnosis, compared with patients who underwent transplantation after a longer period of disease. In addition, younger patients (aged < or = 20 years) were more likely to survive than older patients (aged > 20 years). Thus, for patients with an HLA-matched, unrelated donor, a TBI dose of 200 cGy (in combination with CY/ATG) was sufficient to allow for engraftment without inducing prohibitive toxicity. As in previous studies, patient age and pretransplantation disease duration remain important prognostic factors.Biol Blood Marrow Transplant 2001;7(4):208-15

The effect of inter-unit HLA matching in double umbilical cord blood transplantation for acute leukemia

The effects of inter-unit HLA-match on early outcomes with regards to double cord blood transplantation have not been established. Therefore, we studied the effect of inter-unit HLA-mismatching on the outcomes of 449 patients with acute leukemia after double cord blood transplantation. Patients were divided into two groups: one group that included transplantations with inter-unit mismatch at 2 or less HLA-loci (n=381) and the other group with inter-unit mismatch at 3 or 4 HLA-loci (n=68). HLA-match considered low resolution matching at HLA-A and -B loci and allele-level at HLA-DRB1, the accepted standard for selecting units for double cord blood transplants. Patients’, disease, and transplant characteristics were similar in the two groups. We observed no effect of the degree of inter-unit HLA-mismatch on neutrophil (Hazard Ratio 1.27, P=0.11) or platelet (Hazard Ratio 0.1.13, P=0.42) recovery, acute graft-versus-host disease (Hazard Ratio 1.17, P=0.36), treatment-related mortality (Hazard Ratio 0.92, P=0.75), relapse (Hazard Ratio 1.18, P=0.49), treatment failure (Hazard Ratio 0.99, P=0.98), or overall survival (Hazard Ratio 0.98, P=0.91). There were no differences in the proportion of transplants with engraftment of both units by three months (5% after transplantation of units with inter-unit mismatch at ≤2 HLA-loci and 4% after transplantation of units with inter-unit mismatch at 3 or 4 HLA-loci). Our observations support the elimination of inter-unit HLA-mismatch criterion when selecting cord blood units in favor of optimizing selection based on individual unit characteristics

EZH2 modifies sunitinib resistance in renal cell carcinoma by kinome reprogramming

Acquired and intrinsic resistance to receptor tyrosine kinase inhibitors (RTKi) represent a major hurdle in improving the management of clear cell renal cell carcinoma (ccRCC). Recent reports suggest that drug resistance is driven by tumor adaptation via epigenetic mechanisms that activate alternative survival pathways. The histone methyl transferase EZH2 is frequently altered in many cancers including ccRCC. To evaluate its role in ccRCC resistance to RTKi, we established and characterized a spontaneously metastatic, patient-derived xenograft (PDX) model that is intrinsically resistant to the RTKI sunitinib but not to the VEGF therapeutic antibody bevacizumab. Sunitinib maintained its anti-angiogenic and anti-metastatic activity but lost its direct anti-tumor effects due to kinome reprogramming, which resulted in suppression of pro- apoptotic and cell cycle regulatory target genes. Modulating EZH2 expression or activity suppressed phosphorylation of certain RTK, restoring the anti-tumor effects of sunitnib in models of acquired or intrinsically resistant ccRCC. Overall, our results highlight EZH2 as a rational target for therapeutic intervention in sunitinib-resistant ccRCC as well as a predictive marker for RTKi response in this disease.This research was funded by Roswell Park Cancer Institute’s Cancer Center Support Grant from National Cancer Institute, NIH P30CA016056 (RP) and a generous donation by Richard and Deidre Turner (RP). This investigation was conducted in-part in a facility constructed with support from Research Facilities Improvement Program Grant Number C06 RR020128-01 from the National Center for Research Resources, National Institutes of Health

Phase II study of etoposide, ifosfamide, and mitoxantrone for the treatment of resistant adult acute lymphoblastic leukemia

Although combination chemotherapy induces complete remission in 60–90% of adults with acute lymphoblastic leukemia, only 20–45% of patients remain in continued remission 5 years from diagnosis. For patients with a short first remission, multiple relapses, or patients with disease refractory to initial induction chemotherapy, few salvage treatments are successful. To improve the results of salvage therapy we studied the efficacy and toxicity of a combination of etoposide (100 mg/m2 IV qd × 5), ifosfamide (1.5 g/m2/d × 5), and mitoxantrone (8 mg/m2/d IV × 3) in 11 adult patients with relapsed or refractory ALL. The median follow‐up of all patients completing therapy is 208 days (30–484+ days). Eight of 11 (73%; 95% confidence interval 45–92%) achieved a complete remission, two patients failed to enter remission, and one patient died of multiorgan system failure shortly after receiving therapy. Median DFS is 96 days and median survival from remission is 234 days. Five patients who achieved CR subsequently relapsed with a median time to relapse of 80 days (50–151 days). Median time to granulocyte > .5 × 109/L was 28 days (21–46 days) and the median time to platelet recovery > 20 × 109/L was 24 days (21–39 days). Although gastrointestinal toxicity was common, no patient developed severe cardiac, hepatic, pulmonary, or neurologic complications. These results demonstrate that the combination of etoposide, ifosfamide, and mitoxantrone can be used as an effective salvage therapy for patients with resistant ALL