Patients Undergoing Stem Cell Transplantation Research Articles

Effects of nonpharmacological interventions on reducing fatigue after hematopoietic stem cell transplantation.

Fatigue is one of the main complaints of patients undergoing allogeneic and autologous hematopoietic stem cell transplantation (HSCT). Since nonpharmacological interventions are cost-effective and causes fewer complications, this study aimed to review the studies performed on the effects of nonpharmacological interventions on fatigue in patients undergoing HSCT during September 2016. MEDLINE, CINAHL, Scientific Information Database, IranMedex, PubMed, ScienceDirect, Scopus, Magiran, and IRANDOC databases were searched using Persian and English keywords. A total of 1217 articles were retrieved, 21 of which were used in this study. Exercise is known as an effective intervention in alleviating physical and mental problems of patients undergoing stem cell transplant. This review-based study showed that nonpharmacological methods such as exercise might be effective in decreasing fatigue in patients undergoing stem cell transplant. There is a multitude of studies on some of the complementary and alternative therapy methods, such as music therapy, yoga, relaxation, and therapeutic massage. These studies demonstrated the positive effects of the aforementioned therapies on reduction of fatigue in patients undergoing stem cell transplantation. All the investigated methods in this study were nonaggressive, safe, and cost-effective and could be used along with common treatments or even as an alternative for pharmacological treatments for the reduction, or elimination of fatigue in patients undergoing stem cell transplantation. Given the advantages of complementary and alternative medicine, conducting further studies on this issue is recommended to reduce fatigue in patients after stem cell transplantation.

Evaluation of a biosimilar granulocyte colony-stimulating factor (filgrastim XM02) for peripheral blood stem cell mobilization and transplantation: a single center experience in Japan.

BackgroundBiosimilar granulocyte colony-stimulating factor (G-CSF) has recently been introduced into clinical practice. G-CSFs are used to mobilize CD34+ cells and accelerate engraftment after transplantation. However, in Asia, particularly in Japan, data for peripheral blood stem cell (PBSC) mobilization by this biosimilar G-CSF are currently lacking. Therefore, the clinical efficacy and safety of biosimilar G-CSF for hematopoietic stem cell transplantation needs to be evaluated in a Japanese context.Materials and methodsThe subjects included two groups of patients with malignant lymphoma and multiple myeloma. All patients received chemotherapy priming for the mobilization of PBSCs. All patients were treated with chemotherapy followed by the administration of either the biosimilar G-CSF, filgrastim XM02 (FBNK), or the originators, filgrastim, or lenograstim.ResultsThere were no significant differences among FBNK, filgrastim, and lenograstim treatments in the numbers of CD34+ cells in harvested PBSCs, the scores for granulocyte/macrophage colony forming units, or for malignant lymphoma and multiple myeloma patients evaluated as separate or combined cohorts. In addition, there were no significant differences in safety, side effects, complications, or the time to engraftment after autologous hematopoietic stem cell transplantation.ConclusionBiosimilar FBNK shows the same efficacy and safety as originator G-CSFs for facilitating bone marrow recovery in Japanese malignant lymphoma and multiple myeloma patients undergoing stem cell transplantation. In addition, it is less expensive than the originators, reducing hospitalization costs.

Nutritional support practices in hematopoietic stem cell transplantation centers: A nationwide comparison

ObjectiveIn 2009, international nutritional societies published practice guidelines on screening and nutritional support for patients undergoing stem cell transplantation. Little is known about how these guidelines are implemented in clinical practice. We performed a nationwide survey with the aim of understanding current practice patterns, differences between clinical practice, and international recommendations as well as barriers to the use of nutritional therapy. MethodsWe performed a qualitative survey including all centers across Switzerland offering allogeneic (n = 3) or autologous (n = 7) stem cell transplantation. We focused on in-house protocols pertaining to malnutrition screening, indications for nutritional support, types of nutritional therapy available and provided, and recommendations regarding neutropenic diets. ResultsAll centers offering allogeneic, and most of the centers offering autologous transplantation, had a malnutrition screening tool, mainly the nutritional risk score (NRS 2002) method. Only one center does not provide nutritional support. There is wide variation regarding start and stop of nutritional therapy as well as route of delivery, with five centers recommending parenteral nutrition and five centers recommending enteral nutrition as a first step. Although all centers offering allogeneic transplantation, and approximately every other autologous transplant center, used a neutropenic diet, specific recommendations regarding the type of food and food handling showed significant variation. ConclusionThis Swiss survey found wide variation in the use of nutritional therapy in patients undergoing stem cell transplantation, with low adherence overall to current practice guidelines. Understanding and reducing barriers to guideline implementation in clinical practice may improve clinical outcomes. Close collaboration of centers will facilitate future research needed to improve current practice and ensure high quality of treatment.

Minimal incidence of neurotoxicity without prophylaxis during busulfan-based conditioning regimen in patients undergoing stem cell transplantation.

Busulfan (Bu), an alkylating agent, has been used in pre-transplant conditioning regimens since the 1950s, due to its potent myeloablative effect. Questions have been raised regarding oral or intravenous formulations, although both are known to be associated with serious side effects, including hepatic veno-occlusive disease, and neurotoxicity. The administration of anticonvulsant prophylaxis has become more common during high-dose Bu-based conditioning regimen; however, anticonvulsants can interfere with Bu pharmacokinetics and may have their own side effects, which can affect the outcome of the transplant. Our objective was to analyze the incidence of neurotoxicity in patients who underwent stem cell transplantation with high-dose Bu-based conditioning regimens without anticonvulsant prophylaxis. Ninety-seven patients were included, either having received a dose of 12mg/kg (n=73) for allogeneic transplantation or 16mg/kg (n=24) for autologous transplantation. The incidence of seizures was 0.01%. We conclude that anticonvulsant prophylactic regimens may be unnecessary, and reduction of their use may help to avoid potential drug interactions and undesired side effects.

Cancer testis antigen MAGE C1 can be used to monitor levels of circulating malignant stem cells in the peripheral blood of multiple myeloma patients.

Monitoring the levels of malignant disease-causing cells in multiple myeloma, as opposed to the clinical symptoms alone, is an important move forward in the management of this disease. While current methods including multiparametric flow cytometry and PCR analysis of the clonal plasma cells can be used in a patient-specific manner, their use is limited and the fundamental malignant progenitor cell is not being monitored. The expression of cancer testis antigen MAGE C1 has been linked to the malignant stem cell in this disease, and thus, we investigated the use of both flow cytometric and qRTPCR approaches to monitor its expression as an alternative monitoring methodology in this pilot study. We compared the levels of MAGE C1 in the peripheral blood to serum M protein and serum beta 2 microglobulin levels at 3-monthly intervals over a 2-year period, for 12 patients on chemotherapy regimens and 4 patients undergoing stem cell transplantation. The analysis indicated that the novel flow cytometric analysis of MAGE C1 expression in the peripheral blood was extremely relevant as a potential minimal residual disease-monitoring tool. Expression of this cancer testis antigen was detectable in all patients throughout treatment, with comparable increases and decreases to serum M protein and/or serum beta 2 microglobulin, but with the advantage of being able to detect disease at a more sensitive level. Furthermore, due to the increased sensitivity, the ability to pre-empt disease relapse before clinical changes were evident, was preliminarily indicated. The qRTPCR approach showed potential as a monitoring tool in the chemotherapy patient cohort, with the mRNA MAGE C1 levels following a similar pattern of expression observed in the flow cytometry analysis.

Disseminated herpes zoster infection initially presenting with abdominal pain in patients with lymphoma undergoing conventional chemotherapy: A report of three cases.

Visceral disseminated varicella zoster virus (VZV) disease has a high mortality rate, and occurs in immunocompromised hosts, mostly subsequent to allogeneic stem cell transplantation. Only a few cases of this disease that onset during conventional chemotherapy in patients with lymphoma have been reported. The present study reports the cases of 3 patients with disseminated and visceral VZV infection undergoing treatment for follicular lymphoma, diffuse large B-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified. All 3 patients presented with initial symptoms of abdominal pain, and 2 patients demonstrated syndrome of inappropriate antidiuretic hormone and hepatitis. All patients developed widespread cutaneous dissemination, and all had a low cluster of differentiation 4 cell count or lymphocyte count at the time of VZV diagnosis and at least 4 month prior. With intravenous systemic acyclovir therapy (Cases 1 and 3, 1500 mg/day; Case 2, 750 mg/day), the patients achieved complete recovery by day 14 of therapy. Visceral disseminated VZV infection is not limited to patients undergoing stem cell transplantation, and may present with abdominal pain with or without skin eruption. Visceral infection may take a poor clinical course, therefore, in patients with prolonged duration of low lymphocyte count and/or long-term use of steroids, the prophylactic use of acyclovir may be considered.

Romidepsin enhances the cytotoxicity of fludarabine, clofarabine and busulfan combination in malignant T-cells

Novel approaches to pre-transplant conditioning are needed to improve treatment of advanced T-cell malignancies. We investigated the synergism of fludarabine (Flu), clofarabine (Clo), busulfan (Bu), and romidepsin (Rom) in T-cell lines and patient-derived cell samples. [Flu+Clo+Bu+Rom] had combination indexes of 0.4–0.5 at ∼50% cytotoxicity in PEER and SUPT1 cells, suggesting synergism. Drug exposure resulted in histone modifications, DNA-damage response (DDR), increased reactive oxygen species (ROS), decreased glutathione (GSH) and mitochondrial membrane (MM) potential, and apoptosis. Similar activation of DDR and apoptosis was observed in patient samples. The PI3K-AKT-mTOR, NFκB, Raf-MEK-ERK, JAK-STAT and Wnt/β-catenin pro-survival pathways were inhibited by the 4-drug combination. The SAPK/JNK stress pathway was activated. A novel finding was the down-regulation of the drug transporter MRP1. We propose the following mechanisms of synergism: Flu, Clo and Rom induce histone modifications and chromatin remodeling, exposing DNA to Bu alkylation; the increased production of ROS, due to drug-mediated stress response and decreased GSH, damages the MM causing leakage of pro-apoptotic factors; down-regulation of MRP1 increases intracellular Bu concentration and exacerbates the DDR; and inhibition of multiple survival pathways. Our results provide the basis for a clinical trial to evaluate [Flu+Clo+Bu+Rom] as part of conditioning regimen for refractory T-cell malignancy patients undergoing stem cell transplantation.

The Effects of Oral Cryotherapy on Chemotherapy-Induced Oral Mucositis in Patients Undergoing Autologous Transplantation of Blood Stem Cells: A Clinical Trial.

BackgroundOral mucositis is one of the irritating side effects of chemotherapy in patients undergoing bone marrow transplantation. However, up until now, the common methods of oral mucositis therapy have failed to show significant effects.ObjectivesThe aim of this study was to investigate the effects of local cryotherapy on the intensity of chemotherapy-induced oral mucositis in autologous bone marrow transplantation patients.Patients and MethodsIn this single, blinded, randomized clinical trial, 29 patients undergoing stem cell transplantation in Iran were selected by convenience sampling, and randomly allocated to control (n = 13) and intervention groups (n = 16). In the intervention group, cryotherapy was applied, while the control group received a normal saline mouthwash. The severity of the mucositis and neutrophil rate were investigated in five periods, based on the world health organization (WHO) scales. The data were analyzed using descriptive statistics, the Mann-Whitney test, repeated measures analysis of variance (ANOVA), and linear regression.ResultsIn both groups, the mucositis reached its peak intensity on the 7th day, and the least intensity was obtained on the 21st day. The neutrophil rate reached the minimum value on the 7th day, then increased up to the 21st day. The two groups showed no significant differences between the mucositis severity on the 14th and 21st days (P = 0.164), while the severity of the mucositis in the cryotherapy group was significantly less than that in the saline mouthwash group (1.81 < 2.54 and 0.13 < 0.92, respectively) on the 7th and 14th days (P < 0.05). There was no significant difference in the neutrophil rate between the groups.ConclusionsThe results showed that cryotherapy is more effective than the saline mouthwash in reducing the severity of mucositis. This method is recommended for the prevention of mucositis in bone marrow transplantation.

Microbiota Manipulation With Prebiotics and Probiotics in Patients Undergoing Stem Cell Transplantation.

Hematopoietic stem cell transplantation (HSCT) is a potentially life-saving therapy that often comes at the cost of complications such as graft-versus-host disease and post-transplant infections. With improved technology to understand the ecosystem of microorganisms (viruses, bacteria, fungi, and microeukaryotes) that make up the gut microbiota, there is increasing evidence of the microbiota's contribution to the development of post-transplant complications. Antibiotics have traditionally been the mainstay of microbiota-altering therapies available to physicians. Recently, interest is increasing in the use of prebiotics and probiotics to support the development and sustainability of a healthier microbiota. In this review, we will describe the evidence for the use of prebiotics and probiotics in combating microbiota dysbiosis and explore the ways in which they may be used in future research to potentially improve clinical outcomes and decrease rates of graft-versus-host disease (GVHD) and post-transplant infection.

Posterior Reversible Encephalopathy Syndrome in Beta Thalassemia Major Transplants: A Single Center Experience

Background: Posterior reversible encephalopathy syndrome (PRES) is a neurological syndrome characterized by clinical finding of hypertension, seizures, behavioral changes and altered vision, coupled with MRI abnormalities, known to occur after hematopoietic stem cell transplantation, potentially associated with calcineurin inhibitors. There is limited literature on the clinical and radiological findings in patients with PRES undergoing transplant for beta thalassemia major.Method: A Retrospective analysis of the incidence and characteristics of PRES was performed on transplants done between November 2008 and May 2015. This study assessed the frequency, etiology, clinical and imaging characteristics in patients undergoing stem cell transplantation for beta thalassemia major.Results: A total of 88 bone marrow transplants (BMT) were performed for various indications and among them 39 transplants were for patients with thalassemia major. The median age among the beta thalassemia group was 9 years (range 2-18). Two different regimens were used for thalassemia. Table: 1 Cyclosporine A (CSA) and short course methotrexate were used as graft versus host disease (GVHD) prophylaxis in all allogeneic transplants.A total of 6 (6.7%) patients developed PRES. Two (4%) were among non-thalassemia transplants and 4 (10%) were among thalassemia transplants. (p= 0.276).Among the beta thalassemia transplants, 2 (7%) of them underwent matched related donor (MRD) and 2 (22%) had matched unrelated donor (MUD) transplants. All patients who developed PRES belonged to either Pesaro class II or III risk group. Table 1.High blood pressure recordings above 95th centile were noted in all the patients prior to the onset of seizure and all of them (100%) complained about persisting head ache. Two patients (50%) had visual hallucinations and one of them had transient loss of vision with no ophthalmic findings.MRI changes were seen among 3 patients (75%). Of the patients who had radiological findings, T2 hyper-intensive white matter changes were present in frontal 1 (25%), parietal 3 (75%), occipital 3 (75%), and thalamus 1 (25%). Abnormalities were bilateral all in all patients who had MRI findings, but not necessarily symmetrical. None of the patients had hemorrhage or grey matter changes. The etiological factor for 3 (75%) patients was calcineurin inhibitor (CNI), CSA and the symptoms reverted on discontinuation of CSA. An increased level of CSA was noted only in on patient with a level of 358µg/L (range 131 - 358µg/L). One patient had the seizure with MRI changes following stem cell product infusion.The occurrence of PRES was not associated with previous history of seizures in any of the patients. Time to PRES ranged between 53 to 60 days in patients on calcineurin inhibitors. All patients made a complete recovery within 24-48 hours and were continued on antiepileptics. However, one patient died after status-epilepticus and brain stem injury while on tapering doses of leviteracetam at 6 months post-transplant.Conclusion: It is important to promptly recognize this syndrome based on the post-transplant day, clinical history of head ache, hypertension, visual abnormalities and MRI findings. Early imaging, withdrawal of calcineurin inhibitors, tight blood pressure control and initiation of anticonvulsants in high risk thalassemia transplants may be helpful reducing the incidence. By analyzing larger databases it may be helpful to develop diagnostic criteria and scoring for early diagnosis and intervention.Table 1Transplant indications, types and risk stratification and conditioning regimens.Variablen (%)Total transplants88 (100)Non Thalassemia49 (56)Thalassaemia Class I Class II Class III MRD MUD39 (44) 3 (8) 9(23) 27 (69) 30 (77) 9 (23)Conditioning regimen for thalassemiaN = 39Thiotepa, Treosulfan and Fludarabine36 (92)Busulphan, Cyclophosphamide, ATG3 (8)PRESN=6Non-Thalassemia Thalassemia2 (6.7%) 4 (10%) p=0.276Etiology among thalassemia transplantsCNI Stem cell product infusionN=4 3 (75%) 1 (25%) DisclosuresNo relevant conflicts of interest to declare.

Hemophagocytic Lymphohistiocytosis (HLH) in 44 Adults: Results from the Retrospective Polish Registry

▪IntroductionHemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening syndrome of extreme hyperinflammation. It does not self-limit and needs to be stopped by effective treatment. This reaction can be triggered by numerous factors, including infection, malignancy and autoimmune disease. HLH used to be diagnosed in children, but in last few years more and more adults with this syndrome are treated. This raising awareness enabled creating retrospective registry of adult HLH patients in Poland.MethodsA multicenter retrospective analysis of adult (≥18 years) patients was performed. Inclusion criteria were based on the HLH-2004 protocol.ResultsForty four adult (median age 34, range 18-80) patients from 13 clinical centers were reported. The gender ratio was balanced (M/F: 23/21). Patients fulfilled on the average 5.2 of HLH-2004 criteria. Due to the lack of possibility of sCD25 and NK activity testing in majority of centers only 6 criteria were actually evaluated. Also 6 patients with strong clinical suspicion (e.g. recurrent HLH) fulfilling 4 out of 6 available criteria were included. The most frequent triggering factor was malignancy (14/44) with lymphoma (T-cell 6/14, B-cell 4/14) being the most common. Infection-associated HLH was present in 13 patients, most of which was attributed to EBV (11/13; additionally CMV and B19 occurred). One patient suffered from both T-lymphoma and EBV infection. The most frequent autoimmune diseases identified were Still's disease (n=3) and systemic lupus erythematosus (n=2). In 11 patients clear triggering factor could not be identified. Three patients underwent liver transplantation.Baseline characteristics of all patients are shown in Table 1. Briefly, almost all patients presented with extreme hyperferritinemia, fever, splenomegaly. Other Important features are liver involvement and coagulopathy.Majority of patients were treated according to HLH-2004 protocol, except of patients with malignancy treated with disease-specific chemotherapy regimens (with emphasis on inclusion of etoposide if appropriate). None of the patients underwent stem cell transplantation (SCT) as HLH therapy; one patient had HLH triggered by EBV reactivation after alloSCT.Median survival was 66 days (Fig.1), 39% of patients survived with median observation of 21 months (3-98).ConclusionsHeterogeneity of HLH syndrome was confirmed in Polish population, with malignancy and EBV infection being the most frequent triggering factors.Awareness of HLH in adults is raising, but it should be fostered as HLH is still underdiagnosed. Further studies are needed to deepen our knowledge about HLH in adults.Analysis of additional, newly diagnosed cases is ongoing and will be presented at the meeting.Table 1Baseline patient characteristicsCharacteristic[unit](n)%MedianRangeFever(n=44)97.7Splenomegaly(n=44)90.9Hemophagocytosis(n=41)70.7Hyperferitinemia[µg/l](n=44)10014280846-126680Hemoglobin[g/dl](n=44)8.36.1-13.9Neutrophil count[G/l](n=41)1.10-173Platelet count[G/l](n=44)434-349Triglycerides[mg/dl](n=38)31674-1559Fibrinogen[mg/dl](n=43)16630-901PT[s](n=30)15.99-46.6APTT[s](n=39)3622-86.8CRP[mg/l](n=40)40.10.4-373LDH[U/l](n=39)970195-13160AST[U/l](n=39)15016-16280ALT[U/l](n=40)10018-12390Total Bilirubin[mg/dl](n=37)3.70.34-25.6PT indicates Prothrombin Time; APTT, Activated Partial Thromboplastin Time; CRP, C-Reactive Protein; LDH, lactate dehydrogenase; AST, aspartate aminotransferase; ALT, alanine aminotransferase [Display omitted] DisclosuresKnopinska-Posluszny:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Teva: Other: travel, accommodation, Speakers Bureau. Wiktor-Jedrzejczak:Amgen, Inc.: Research Funding; Onconova: Other: Advisory Board; Novartis: Research Funding; Pfizer: Other: Advisory Board; Roche: Other: Advisory Board, Research Funding; Jansen: Other: Advisory Board; Celgene: Other: Advisory Board.

Assessment of NPM1 Type a Mutation Burden By Digital Droplet PCR As a Marker of Minimal Residual Disease in Acute Myeloid Leukemia Patients Undergoing Stem Cell Transplantation

Introduction: Minimal residual disease (MRD) monitoring after achievement of hematologic complete remission (CR) in patients (pts) with acute myeloid leukemia (AML) aids in identifying pts at risk of relapse. Evaluating MRD markers for clinical practice is crucial for improving outcomes in AML.Since mutations in the gene encoding Nucleophosmin (NPM1 mut) occur early in leukemogenesis & are relatively stable during disease course, they represent suitable markers for MRD monitoring. Approximately 30% of AML pts harbor NPM1 mut of which approximately 80% are type A. Some studies already demonstrated the feasibility to use NPM1 mut as MRD markers in AML pts and showed NPM1 mut MRD positivity at different time-points during disease course to be predictive for AML relapse.Hematopoietic stem cell transplantation (HCT) is a consolidating therapy option offering potential cure to AML pts. Here, we tested the feasibility to use NPM1 mut type A as MRD marker in pts receiving HCT applying digital droplet polymerase chain reaction (ddPCR) methodology. This novel technique offers high sensitivity, specificity & absolute quantification without the need of standard curves, promising inter-laboratory comparability. At the same time cost effectiveness may be superior to standard qualitative real-time PCR making ddPCR a promising new application.Methods: We analyzed 134 pts (median age 64 years [y], range 38-76y) who received HCT after non-myeloablative conditioning (NMA, 3x30mg/m2 Fludarabine on days -4 to -1 & 2Gy total body irradiation) in CR in our institution between 2000 & 2013. Donors were human leukocyte antigen (HLA)-matched related (n=23; 17.1%) or HLA-matched (n=79; 63.7%) or mismatched (≥1 antigen; n=32; 23.9%) unrelated. Median follow-up was 4.3y for pts alive.NPM1 mut status was assessed in diagnostic bone marrow (BM) samples by Sanger sequencing of the mutation hot spot in exon 12. All pts with NPM1 mut type A & available BM samples at the time of NMA-HCT (within 28 days before HCT) were analyzed by ddPCR. cDNA was applied to a duplex assay measuring NPM1 wild type (wt) & mutation type A simultaneously using fluorescent labeled probes. The mutation burden, defined as % mut type A copies/wt copies ratio, was normalized to ABL. Samples with NPM1 mut type A burden >0.01% were defined as MRD positive (MRD+) & samples with mutation burden ≤0.01% or <3 positive droplets were defined as negative according to manufacturer's recommendations.Results: We identified 42 AML pts (24.8%) with NPM1 mut of whom 24 pts had a type A mutation & BM samples at the time of NMA-HCT available. In this set 16 pts (66.7%) were classified to have favorable risk according to European LeukemiaNet (ELN) classification, 7 pts intermediate-I (29.2%) & 1 patient intermediate-II (4.1%) risk. 8 of the 16 pts harbored a FLT3 -ITD.In 4 pts NPM1 mut type A MRD was detectable at the time of NMA-HCT of which 3 pts experienced relapse. The fourth patient died 3 months after NMA-HCT due to transplantation-related complications & no further MRD time-points were available for analysis. In our cohort all clinical relapses occurred within 6 months after HCT. Two pts relapsed without detectable NPM1 mut type A at NMA-HCT. For these two pts there were no follow-up samples for further MRD monitoring after NMA-HCT available. MRD+ status at the time of NMA-HCT associated with a significantly lower cumulative incidence of relapse (P=0.001, Figure 1A) & shorter overall survival (P=0.003, Figure 1B).Conclusion: Our data demonstrate that ddPCR is a feasible method to determine the NPM1 mut type A burden by absolute quantification. Additionally, we showed the applicability of NPM1 mut type A as MRD marker in AML pts at the time of NMA-HCT. 3 out of 5 pts with clinical relapse were MRD+ at NMA-HCT. Assessing the NPM1 mut type A MRD status at the time of NMA-HCT & possibly at later time-points after HCT by ddPCR might help to identify pts at high risk of relapse. Our results strengthen the observation to use NPM1 mut for MRD monitoring. Consequently, we aim at expanding the applied ddPCR methodology to other NPM1 mut types & testing the validity in the context of clinical studies at various time points before & after NMA-HCT. [Display omitted] DisclosuresFranke:Novartis: Other: Travel Costs; MSD: Other: Travel Costs; BMS: Honoraria. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

The Charlson Comorbidity Index Predicts Survival Following Tyrosine Kinase Inhibitor Treatment in Chronic Myeloid Leukemia Patients

Background: Comorbidity may influence the treatment and long-term quality of life of chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). The Charlson Comorbidity Index (CCI) assesses comorbidity by taking into account the severity of 19 precedent comorbid conditions [J Chron Dis 1987; 40: 373]. The CCI was originally introduced as a measure of the mortality risk of general hospitalized patients, and it can estimate the risk of morbidity in a patient with any medical background. The CCI has been validated to predict patients' life expectancy in various underlying diseases, and it is widely used for both hospitalized patients and outpatients. We evaluated the risk of comorbidity at the diagnosis of CML to determine whether treatment with tyrosine kinase inhibitors (TKIs) results in longer survival in a cohort of Japanese patients.Patients and method: We used a chart review to survey CML patients diagnosed between November 2001 and December 2012 in Kagawa, Japan, where we collected all of the patients based on their registration in another population-based study. Inclusion criteria were (1) diagnosis of CML in the chronic phase during the study period and (2) treatment by TKIs at any point of the study period. Patients of all ages were included. The available TKIs were imatinib, nilotinib and dasatinib. We did not exclude patients treated with two or more TKIs. We used the CCI to evaluate concomitant underlying disease at diagnosis, and we calculated the Sokal and Hasford scores to compare the predictability of prognosis with the CCI at diagnosis. We used the Sokal and Hasford scores as the standard reference.Results: Eighty (47 male, 33 female) cases were enrolled (median age 56 yrs, range 6-89 yrs). The distribution of CCI scores at diagnosis were 2-11 (median 2). The initial treatment was started in 73 cases by imatinib, two cases by nilotinib, and four by dasatinib (one is unknown). Only one patient underwent stem cell transplantation after 2-yr treatment by imatinib, because of the development of myelodysplastic syndrome (this case was not censored.) As of the last follow-up, the treatment responses were 46 major molecular responses (MMRs), 12 complete cytogenetic responses (CCyRs) and 14 complete hematological responses (CHRs). Seventy-five percent of the cases (60/80) achieved CCyR at 12 mos after TKI administration. We observed only five deaths during the 55.5-mos median follow-up period (0.3-217 mos; 3 pneumonia, 1 cancer and 1 unknown cause). The number of patients according to the given CCI comorbidity risk categories are presented in Table 1. The patient numbers in the risk categories (low/intermediate/high) per the Sokal and Hasford scores were 33/27/7 and 21/43/3, respectively. The CCI scores were significantly correlated with the Sokal and Hasford scores (R >0.5). Twenty-seven cases with a CCI score ≥3 (52 cases had CCI <2) had significantly poor survival both from diagnosis (log rank, P =0.0136) and from TKI treatment (P =0.0025). The most common CCI comorbidity factor was 'diabetes without organ failure.' The most serious comorbidity was 'metastatic cancer,' seen in four cases. CCI scores were inversely associated with overall survival (R = −0.11).Discussion: In CML, concomitant comorbidity at diagnosis is more strongly associated with survival, especially after TKI treatment compared to after diagnosis. This suggests that TKI treatment may influence patients' health conditions by contributing to the induction of adverse events. Thus, the clinical impact of CCI for CML patients treated with TKIs is supplemental, but CCI is useful to take care of the patient.Table 1Numbers of patients according to the given comorbidity risk categories of CCIA. Myocardial Infarction (1 point)1B. Congestive Heart Failure (1 point)3C. Peripheral Vascular Disease (1 point)1D. Cerebrovascular Disease (1 point)1E. Dementia (1 point)5F. COPD (1 point)4G. Connective Tissue Disease (1 point)1H. Peptic Ulcer Disease (1 point)2I. Diabetes Mellitus (1 point uncomplicated, 2 points if end-organ damage)7 and 2J. Moderate to Severe Chronic Kidney Disease (2 points)2K. Hemiplegia (2 points)1L. Leukemia (2 points)80M. Malignant Lymphoma (2 points)0N. Solid Tumor (2 points, 6 points if metastatic)2 and 3O. Liver Disease (1 point mild, 3 points if moderate to severe)3 and 0P. AIDS (6 points)0 DisclosuresNo relevant conflicts of interest to declare.

Potentially Avoidable Hospitalizations in Older Patients with Acute Myeloid Leukemia (AML)

Background: Many older adults (≥60) with AML have a poor prognosis and spend a high portion of their life from diagnosis until death in the hospital. Using a large cohort, we examined the reasons for hospitalizations and identified those which are potentially avoidable.Methods: We conducted a retrospective analysis of 329 consecutive patients (≥60) diagnosed with AML between 5/1/2005 and 12/31/2011 at two major tertiary care hospitals to examine the reasons for hospitalizations during treatment. Practicing physicians used a consensus-driven medical record review process to identify primary reason for each hospitalization and categorize it as "potentially avoidable" or "not avoidable" based on a novel adaptation of the Graham's criteria for potentially avoidable hospital admissions. We compared the rate of potentially avoidable hospitalizations between older patients receiving intensive chemotherapy (n=197) versus non-intensive chemotherapy (n=132) using multivariate logistic regression analysis controlling for age, gender, marital status, disease risk, comorbidities, and the receipt of stem cell transplantation.Results: We evaluated 1040 hospitalizations after the diagnosis of AML in 329 unique patients. The median age was 69.9 years [range 60-90] and the median number of hospitalizations was 4.2 [range 0-18]. 33.1% (109/329) of patients underwent stem cell transplantation. The most common primary reasons for hospitalizations were: fever/infection (38.0%), planned hospitalizations for chemotherapy or transplantation (37.7%), and uncontrolled symptoms (9.8%). We identified 180/1040 hospitalizations (17.4%) as potentially avoidable; among these, 47.8% were due to premature hospital discharge, 18.9% could have been managed in the outpatient setting, and 16.1% were due to failure of timely outpatient follow-up. Potentially avoidable hospitalizations represented 12.9% (76/589) and 23.1% (10/451) of hospitalizations among patients who received intensive chemotherapy and non-intensive chemotherapy, respectively. In multivariate logistic regression analysis, the receipt of non-intensive chemotherapy was associated with higher risk of potentially avoidable hospitalization [OR 2.01, 95% CI 1.27-3.20, P = 0.003].Conclusions: Although many hospitalizations in older patients with AML are unavoidable and driven by the illness course and its treatment, a substantial proportion are potentially avoidable. Patients with AML undergoing non-intensive chemotherapy are at higher risk of having potentially avoidable hospitalization. Future interventions to reduce health care utilization in this population are needed, especially among those who are treated with non-intensive chemotherapy. DisclosuresSteensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. LeBlanc:Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Epi-Q: Consultancy; Flatiron: Consultancy; Helsinn Therapeutics: Honoraria, Research Funding. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Merck: Other: Advisory Board participation; Seattle Genetics: Other: Advisory Board participation, Research Funding. DeAngelo:Amgen: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Agios: Consultancy; Bristol Myers Squibb: Consultancy. Stone:Merck: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Novartis: Research Funding; Agios: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy; Roche/Genetech: Consultancy; AROG: Consultancy; Pfizer: Consultancy; Juno: Consultancy; Celator: Consultancy. Chen:Bayer: Consultancy, Research Funding.

Potentially avoidable hospitalizations in older patients with acute myeloid leukemia (AML).

206 Background: Many older adults ( ≥ 60) with AML have a poor prognosis and spend a significant portion of their life from diagnosis until death in the hospital. We examined the reasons for hospitalizations and identified potentially avoidable hospitalizations. Methods: We conducted a retrospective analysis of 200 patients ( ≥ 60) diagnosed with AML between 1/1/2006 and 10/30/2011 at two hospitals in Boston to examine the reasons for hospitalizations during treatment. Practicing physicians used a consensus-driven medical record review process to identify primary reason for each hospitalization and categorize it as “potentially avoidable” or “not avoidable” based on a novel adaptation of the Graham’s criteria for potentially avoidable hospital admissions. We compared the rate of potentially avoidable hospitalization between older patients receiving intensive chemotherapy (n = 124) versus non-intensive chemotherapy (n = 76) using Fisher’s Exact test. Results: We evaluated 627 hospitalizations after the diagnosis of AML in 200 unique patients. The median age was 69 years [range 60-90] and the median number of hospitalizations was 4.0 [range 0-18]. 33.2% of patients underwent stem cell transplantation. The most common primary reasons for hospitalizations were: fever/infection (38.3%), planned hospitalizations for chemotherapy or transplantation (35.9%), and uncontrolled symptoms (10.5%). We identified 108/627 hospitalizations (17.2%) as potentially avoidable. Among potentially avoidable hospitalizations, 40.7% were due to premature hospital discharge, 22.2% could have been managed in the outpatient setting, 13.9% failed to have timely outpatient follow-up, and 13% were due to patients’ medication non-adherence. There were no differences in potentially avoidable hospitalizations between patients receiving intensive vs. non-intensive chemotherapy (16.9% vs. 17.8%, P = 0.83). Conclusions: Most hospitalizations in older patients with AML are unavoidable and driven by the illness course and its treatments. However, a minority of hospitalizations is potentially avoidable and should be the focus of future interventions to reduce health care utilization and the burden of AML on this population.

Evaluating the frequency of vital sign monitoring during blood transfusion: an evidence-based practice initiative.

Patients with cancer are often dependent on blood transfusions during treatment. Frequent vital sign monitoring during transfusions may interrupt sleep and the patient's ability to ambulate or participate in unit activities. Relying heavily on vital sign findings may also overshadow unmeasurable symptoms of transfusion reaction. The aim of this evidence-based practice initiative was to examine the evidence regarding the optimum frequency of vital sign monitoring for patients undergoing stem cell transplantation receiving blood products and to amend policy and practice to be consistent with the literature. AT A GLANCE : Patients with cancer frequently require transfusion support during treatment.Inconsistencies exist in recommendations for the frequency of vital sign monitoring during transfusion.Examining best practice guidelines suggests that less frequent vital sign monitoring may be appropriate if coupled with thoughtful physiologic assessment.

Contribution of Clostridium difficile infection to the development of lower gastrointestinal adverse events during autologous stem cell transplantation.

Lower gastrointestinal (GI) adverse events (LGAE) are common afflictions of patients undergoing stem cell transplantation (SCT). Unfortunately, the pathophysiology remains poorly characterized. Emerging data suggest a prominent role of intestinal microbiota; however, contributions of pathogenic gut microbiota such as Clostridium difficile are not well defined. We performed a genome-wide association study (GWAS) to investigate clinical and genetic factors associated with development of LGAE. A total of 972 patients undergoing autologous SCT were graded for LGAE based on Common Terminology Criteria for Adverse Events (v 4.0). Germline DNA material was obtained from leukapharesis products and genotyped using Illumina(®) Whole Genome Genotyping Infinium chemistry and HumanOmni1-Quad Bead chips containing over 1.1 million single nucleotide polymorphisms (SNPs) (Illumina, San Diego, California, USA). Statistical models incorporating clinical factors, genetic factors, and a combination of clinical plus genetic factors were utilized to compare patients who developed severe LGAE (grade 2 or above) and others. Among 972 patients, 459 (47.2%) developed severe LGAE. Baseline hemoglobin and hematocrit, estimated glomerular filtration rate, β2-microglobulin, protocol type, and C. difficile infection (CDI) were associated with severe LGAE on univariate analysis, Genomic comparisons between groups did not reveal any SNPs associated with severe LGAE and neither did incorporation of genetic factors into the clinical model. In addition, 11 candidate SNPs associated with upper GI mucositis were evaluated, alongside clinical factors in a multivariate model. Only CDI was found to be associated with severe LGAE in all models. CDI is a prominent factor in the development of LGAE in patients undergoing autologous SCT.

674. Development of the Retroviral Vector Manufacturing Process for MM-TK Therapy

The MM-TK Drug Product (DP) is a medicinal product used as adjunctive therapy in leukaemia patients undergoing stem cell transplantation. It is constituted of T lymphocytes genetically modified ex vivo with the γ retroviral vector SFCMM-3 Mut2 #48 encoding the HSV-TK Mut2 suicide gene and the cell surface marker ΔLNGFR. During clinical development, different improvements were introduced in retroviral vector (RVV) manufacturing in order to obtain simple and robust processes producing RVV with low level of impurities and high performance in lymphocyte transduction. Single-use bioreactors are currently replacing conventional bioreactors also for mammalian cell culture. They allow to increase biological and process safety by reducing cleaning and sterilization procedures and the risk of cross contaminations. In this context, we are currently evaluating different single-use, closed-system bioreactors for the manipulation of adherent packaging cell lines. A feasibility study is on-going, using a single-use bioreactor based on the 2D multi-tray stacks technology Xpantion system (Pall LifeSciences). This study explores the role of gas control on cell growth and its impact on the RVV quality attributes evaluating key metabolites, as glucose and lactate, and viral titer during cell expansion. In parallel a manufacturing process in 10-layers cell factories (CFs) has been developed and validated. The results obtained with the Am12/SFCMM-3 Mut2 #48 producer cell line grown up to 10 days in XP10 and in XP50 bioreactors showed an infectious viral titer on the reference cell line CEM A3.01, a transduction efficiency on T cells and an impurities level close to those obtained with the CFs.Process development and comparability data will be presented in more detail.

Productivity loss due to premature mortality caused by blood cancer: a study based on patients undergoing stem cell transplantation

IntroductionStem cell transplantation has been used for many years to treat haematological malignancies that could not be cured by other treatments. Despite this medical breakthrough, mortality rates remain high. Our purpose was to evaluate labour productivity losses associated with premature mortality due to blood cancer in recipients of stem cell transplantations. MethodsWe collected primary data from the clinical histories of blood cancer patients who had undergone stem cell transplantation between 2006 and 2011 in two Spanish hospitals. We carried out a descriptive analysis and calculated the years of potential life lost and years of potential productive life lost. Labour productivity losses due to premature mortality were estimated using the Human Capital method. An alternative approach, the Friction Cost method, was used as part of the sensitivity analysis. ResultsOur findings suggest that, in a population of 179 transplanted and deceased patients, males and people who die between the ages of 30 and 49 years generate higher labour productivity losses. The estimated loss amounts to over €31.4 million using the Human Capital method (€480,152 using the Friction Cost method), which means an average of €185,855 per death. The highest labour productivity losses are produced by leukaemia. However, lymphoma generates the highest loss per death. ConclusionsFurther efforts are needed to reduce premature mortality in blood cancer patients undergoing transplantations and reduce economic losses.

MicroRNA-133a engineered mesenchymal stem cells augment cardiac function and cell survival in the infarct heart.

: Cardiovascular disease is the number 1 cause of morbidity and mortality in the United States. The most common manifestation of cardiovascular disease is myocardial infarction (MI), which can ultimately lead to congestive heart failure. Cell therapy (cardiomyoplasty) is a new potential therapeutic treatment alternative for the damaged heart. Recent preclinical and clinical studies have shown that mesenchymal stem cells (MSCs) are a promising cell type for cardiomyoplasty applications. However, a major limitation is the poor survival rate of transplanted stem cells in the infarcted heart. miR-133a is an abundantly expressed microRNA (miRNA) in the cardiac muscle and is downregulated in patients with MI. We hypothesized that reprogramming MSCs using miRNA mimics (double-stranded oligonucleotides) will improve survival of stem cells in the damaged heart. MSCs were transfected with miR-133a mimic and antagomirs, and the levels of miR-133a were measured by quantitative real-time polymerase chain reaction. Rat hearts were subjected to MI and MSCs transfected with miR-133a mimic or antagomir were implanted in the ischemic hearts. Four weeks after MI, cardiac function, cardiac fibrosis, miR-133a levels, and apoptosis-related genes (Apaf-1, Caspase-9, and Caspase-3) were measured in the heart. We found that transfecting MSCs with miR-133a mimic improves survival of MSCs as determined by the MTT assay. Similarly, transplantation of miR-133a mimic transfected MSCs in rat hearts subjected to MI led to a significant increase in cell engraftment, cardiac function, and decreased fibrosis when compared with MSCs only or MI groups. At the molecular level, quantitative real-time polymerase chain reaction data demonstrated a significant decrease in expression of the proapoptotic genes; Apaf-1, caspase-9, and caspase-3 in the miR-133a mimic transplanted group. Furthermore, luciferase reporter assay confirmed that miR-133a is a direct target for Apaf-1. Overall, bioengineering of stem cells through miRNAs manipulation could potentially improve the therapeutic outcome of patients undergoing stem cell transplantation for MI.