bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-Random Integration and Clone Selection by Lentiviral SIN-LTR Vectors.
Authors: Bartholomae Cynthia C. , Deichmann Annette , Schmidt Manfred , Yanez-Munoz Rafael J. , Howe Steven J. , Schmidt Sonja , Prinz Claudia , Thrasher Adrian J. , von Kalle Christof
Published: October 2019

The need for safer gene therapy vectors was highlighted by the occurrence of three cases of retroviral vector-induced leukemia in children after the cure of severe combined immunodeficiency by gene therapy. These severe adverse events enhanced the development of new gene therapy vector systems, which aim to reduce influence of insertions on integrity and expression of genomic host DNA. Lentiviral vectors with self-inactivating (SIN) long terminal repeats (LTRs) have no LTR enhancer activity and are not expected to produce insertional gene activation. In our study we analyzed the integrations sites of three different lentiviral SIN-HIV-based- vectors. These vectors differed in their internal elements (Promotor, Transgene, WPRE) which allowed us to investigate whether internal elements are influencing target site selection and clone survival. A total of 1422 integration sites were analyzed at three different time points (1 day, 30 days, 60 days) after transduction of identical HeLa cells by LAM- PCR. Our results showed similar gene involvement and chromosomal distribution of integration sites for all vector types analyzed, independent of vector composition. 62–63% of the integrations were detected in Refseq genes, 82–86% were found within Refseq genes and their surrounding 10kb. Surprisingly, 271 of 1422 integration sites were clustered as common integration sites (CIS). Computer simulations allowed us to show that this high number of CIS was significantly different from a modeled random distribution of integration sites. Gene ontology analysis showed no difference in significantly overrepresented gene categories between the distinct vector types. Interestingly, we detected a time dependent increase or decrease in significance. Specific gene categories like phosphorylation, protein kinase or ATP binding activity increased in significance from freshly transduced cells (1 day) to 30 days. This observation was even more pronounced at the latest time point analyzed (60 days). Other gene categories showed the exactly opposite effect. Gene ontology analysis of freshly transduced cells showed a significant overrepresentation of genes involved in cell cycle regulation, whereas the analysis of the later time points did not show overrepresentation of this gene category. These results suggest that lentiviral SIN-HIV-based vectors may induce clonal selection in vitro independently of internal vector elements. The character of such effects as well as any putative relevance of such genotoxicity for the in vivo situation will have to be investigated in detail for the role of individual vector/cell type configurations.
Long-Term Polyclonal and Stable Gene Transfer into Rhesus Repopulating Hematopoietic Stem Cells Using a Simian Immunodeficiency Virus-Based Lentiviral Vector System.
Authors: Kim Yoo-Jin , Hussein Nadia L. , Hematti Peiman , Hong Bum-Kee , Calmels Boris , Donahue Robert E. , Hanawa Hideki , Nienhuis Arthur W. , Dunbar Cynthia E.
Published: October 2019

Murine leukemia virus (MLV) vectors have been studied extensively in animal models and utilized for over a decade in clinical trials of gene therapy directed at hematopoietic stem and progenitor cells MLV have a number of limitations, including inefficient transduction of quiescent cells and difficulty in maintaining stable high-level expression. More recently concerns have arisen regarding their safety regarding activation of adjacent proto-oncogenes and resultant leukemogenesis. We have previously reported that lentiviral vectors derived from the simian immunodeficiency virus (SIV) were efficient at transducing rhesus CD34+ cells, resulting in high-level in vivo marking with transduced progeny cells up to one year post-transplantation.(Hanawa et al, 2004) A comparison of vector integration sites in these animals compared to animals receiving MLV-transduced cells revealed different patterns, showing that SIV integrants strongly favored entire transcription units and gene-dense regions of the genome, compared to MLV that favored regions surrounding transcription start sites.(Hematti et al, 2004). Animals receiving MLV-transduced cells had highly non-random engraftment with integrants in or near the the MDS1/EVI1 gene complex. To evaluate long-term safety implications of the SIV vector-mediated CD34+ cell gene transfer, we analyzed the insertional sites in granulocytes, T cell, and B cells from 3 rhesus macaques which were transplanted three years ago with transduced, autologous cytokine-mobilized peripheral blood CD34+ cells. All three animals continued to show significant marking and expression levels in T cells, B cells and granulocytes, with mean GFP + levels of 6.7% (range, 3.3–13.0%), 7.4% (4.2–13.4%) and 5.6% (3.1–10.5%), respectively. Vector insertion site analysis by linear amplification-mediated PCR method at three years continued to show highly polyclonal reconstitution. Subsequent cloning and sequencing data confirmed long-term polyclonality with vector-containing cells and there was no evidence for any worrisome common integration sites, with no integrants detected in the MDS1/EVI1 region, in contrast to results with the MLV vector. These results indicate that the SIV vector system can result in stable and efficient long-term expression in progeny of transduced CD34+ cells, without the worrisome integration profile previously reported in our model with MLV vectors.
Total Body Irradiation, Etoposide, Cyclophosphamide and Autologous Peripheral Blood Stem Cell Transplantation Followed by Randomization to Therapy with Interleukin-2 Versus Observation for Patients with Non-Hodgkin’s Lymphoma: Results of a Phase III Randomized Trial by the Southwest Oncology Group (SWOG 9438).
Authors: Thompson John A. , Fisher Richard I. , LeBlanc Michael L. , Unger Joseph M. , Forman Stephen J. , Stiff Patrick J. , Fefer Alexander
Published: October 2019

Purpose: To determine the effect of post-transplant immunotherapy with Interleukin-2 (IL-2) on the progression-free and overall survival of patients with non-Hodgkin’s lymphoma (NHL) after autologous stem cell transplantation and to assess the toxicity of post-transplant IL-2 therapy.

Patients and Methods: Patients with previously treated low, intermediate, or high grade NHL (except Working Formulation Groups A and I) were treated with high-dose cyclophosphamide, etoposide, and total body irradiation (TBI) and an autologous peripheral blood stem cell transplant (PBSCT). Twenty-eight to 80 days after PBSCT, patients were randomized to treatment with IL-2 versus observation.

Results: Between January 1995 and July 2004, three hundred ninety-four patients with low-grade (n=61) or intermediate-high grade NHL (n=315) were registered at one of 39 SWOG transplant centers. One hundred ninety patients did not proceed to randomization, because of patient refusal (44), grade V toxicity (30), disease progression (28), toxicity (28), or other reasons. Two hundred four patients were randomized to treatment with continuous infusion intravenous IL-2 (9 ×106 units/m2/day for four days followed five days later by 1.6 ×106 units/m2/day for 10 days) versus observation. The 4-year progression-free survival estimate for all eligible patients is 34%, and the 4-year overall survival estimate is 52%. There was no difference in progression-free survival (hazard ratio (HR) of IL-2 to observation = 0.90; p = 0.56) nor in overall survival (HR of IL-2 to observation = 0.88; p = 0.55). There were no deaths related to IL-2 treatment. Grade IV IL-2-related toxicities included hematologic (n=10), cardiovascular (4), renal/bladder (2), flu-like symptoms (1), lung (1), metabolic (1), and neurologic (1) and were reversible in all cases.

Conclusions: These results confirm earlier SWOG findings that a regimen of cylophosphamide, etoposide and TBI followed by PBSCT can be administered to patients with relapsed or refractory NHL with acceptable toxicity and with encouraging progression-free and overall survival. Post-transplant therapy with IL-2 given at this dose and schedule of administration had no significant effect on post-transplant relapse, progression-free survival or overall survival.
Rituximab (Mabthera) Improves the Treatment Results of DHAP-VIM-DHAP and ASCT in Relapsed/Progressive Aggressive CD20+ NHL. A Prospective Randomized HOVON Trial.
Authors: Vellenga Edo , Notenboom Annelise , van ‘t Veer Mars , Zijlstra Josée , Fibbe Willem E. , van Oers Rien , van Imhoff Gustaaf W. , Lugtenburg Elly , Huijgens P.C.
Published: October 2019

A total of 239 patients with relapsed/progressive aggressive CD20+ NHL after/during adriamycin containing regimens, were recruited to the randomized HOVON-44 trial comparing DHAP-VIM-DHAP followed by BEAM and autologous stem cell re-infusion (ASCT)(“DHAP-arm”) with DHAP-VIM-DHAP in conjunction with Rituximab (375 mg/m2) and ASCT (“R-DHAP arm”). Of the included patients, 202 were evaluable and randomized to the DHAP arm (n=101) or R-DHAP arm (n=101). Only patients with CR/PR after two courses of intensive chemotherapy were eligible for ASCT. Patients were well balanced for risk factors. In both arms the majority of patients had not been exposed to Rituximab during first line treatment. As of July 2006, median follow-up of all patients still alive is 24.5 months. After two courses of chemotherapy PR/CR was obtained in 49 % of the patients in the DHAP arm and 77% in the R-DHAP arm (p=<.01;intention to treat analysis). Post-transplantation PR/CR was obtained in 41% and 58% of the patients respectively (p=.40). A significant difference between both arms was observed for failure free survival (FFS), disease free survival (DFS) and overall survival (OS) in favor of the Rituximab arm (p<.05, table 1). The less pronounced difference in OS between both arms is most likely due to the fact that non-responding or relapsing patients in the DHAP arm received salvage treatment with a Rituximab containing regimen. Additionally, a subgroup analysis was performed according to type of response to first-line treatment:1) Response duration more than 3 months (n=138); 2) Progression or response duration less than 3 months (n=64). Within both subgroups, the hazard ratio’s for the endpoints were of equal magnitude (.40–.60), indicating that the beneficial effect of Rituximab existed in both subgroups. In conclusion these results demonstrate that the addition of Rituximab to second line of chemotherapy followed by ASCT results in a significant improved FFS, DFS, and OS in patients with relapsed/progressive aggressive CD20+ NHL.

Table 1 FFS DFS OS *: 2 years estimate DHAP-arm* 21% 46% 48% R-DHAP arm* 52% 82% 62% Hazard ratio .40 .32 .61 p-value log rank test <0.001 0.003 0.03
Content, Accuracy and Quality of Warfarin Patient Information.
Authors: Geerts William H. , Diamantouros Artemis , Bartle Bill , Kim Linda , Selby Rita
Published: October 2019

Background: Warfarin is a very common, narrow therapeutic index drug which requires clear understanding by patients in order to ensure its safe use. Patients are largely educated about warfarin through written information sheets provided by pharmacies. It is critical that these sheets provide all of the essential information about warfarin use in a format that is accurate and understandable.

Objective: The goals of this study were to assess the content and accuracy of warfarin information sheets provided to patients by community pharmacies as well as to assess the reading level of each information sheet.

Methods: A reference standard for warfarin patient information was developed, based on a formal survey of a national group of thrombosis health professionals. Warfarin patient information sheets, distributed by community pharmacies, were compared to the reference standard. Reading level was assessed using two standardized instruments, the Flesch-Kincaid scale and SMOG scale, and compared to the recommended Grade 5 to 6 level for patient information sheets. Patient information booklets, distributed by the producers of warfarin, were also evaluated.

Results: Six different warfarin patient information sheets were distributed by 98% of the community pharmacies in Ontario. On average, these sheets included only 44% of the recommended essential or important knowledge items (range 20–52%), with considerable variability in the content of specific items. Each sheet also contained incorrect information. The average reading level of the information sheets was Grade 11 (range Grade 7 to above Grade 12). On average, the pharmaceutical booklets included 71% of the essential or important information items (range 58–84%).

Conclusions: Patients prescribed warfarin are likely to receive information sheets from a community pharmacy that contain less than half of the information content important to their safe use of warfarin as well as statements that are misleading or incorrect. Furthermore, comprehension of these sheets is limited by a reading level substantially higher than recommended. All six of the information sheets reviewed were derived from an American drug information database and therefore, generalized applicability of these results exists. The information that patients receive about warfarin must be improved and we suggest that a national standard be used.
Cost-Minimization Analysis of Anti-D Immune Globulin Versus Intravenous Immune Globulin for the Initial Treatment of Immune Thrombocytopenic Purpura.
Authors: Wetzel David A. , Tarantino Michael D.
Published: October 2019

Immune Thrombocytopenic Purpura (ITP) is an autoimmune disorder in which opsonized platelets are prematurely destroyed within the spleen. At this time both anti-D immune globulin (anti-D) and intravenous immune globulin (IVIG) are established treatment options for the management of ITP in children and adults. Due to the tremendous increase in demand for IVIG products in the past decade and the subsequent lack of sufficient production a national shortage has emerged. As a consequence, the direct cost and resulting burden on the healthcare payer has risen dramatically for this treatment option. We performed a cost-minimization analysis (CMA) to compare the cost of using anti-D versus IVIG for the initial treatment of non emergent ITP in appropriate patients. A CMA was employed for this economic evaluation because clinical evidence supports the supposition that the efficacies of the treatment options in question are similar. The perspective used for this study was that of the healthcare payer. The study population includes children and adults with non emergent forms of ITP who are both Rh positive and nonsplenectomized. This CMA did not include the cost to the healthcare payer for treatment administration or the incidence and cost of subsequent treatments for each product. The incidence of severe adverse events when using IVIG or anti-D are rare and therefore were not included in this CMA. In this analysis the cost for the non emergent initial treatment of ITP using [Immune Globulin Intravenous (Human)] 10% (Gammagard Liquid 10%) 1gm/kg × 2 days was compared to anti-D (WinRho® SDF Liquid) 50μg/kg × 1 day respectively. We performed a CMA using the same initial dose and duration of IVIG and anti-D dosed at 75μg/kg. And finally we performed a CMA using one day of treatment for both IVIG and anti-D dosed at 75μg/kg. An average patient weight of 75kg was used for initial dose calculations for each product. The average wholesale price (AWP) for each product was used for cost calculations. Gammagard Liquid 10% was selected as the product for IVIG therapy because this product currently holds a large portion of market share for IVIG products in the US. An example CMA calculation was; Gammagard Liquid 10% 1g/kg × 75kg × 2 days × $101.25 – WinRho® SDF 50μg/kg × 75kg × $1.10/μg. The results of these three CMAs when using anti-D versus IVIG for the initial treatment of ITP yielded a cost savings of $11,063.00, $9,000.50 and $1,406.25 respectively. When the CMA calculations were adjusted to use the actual number of vials needed to dispense the final dose of IVIG and anti-D dosed at 75μg/kg, the savings realized was $1,213.75 per dose dispensed. These CMAs have demonstrated the cost benefit of using anti-D for the initial treatment of non emergent ITP in appropriate patients.
Cost-Effectiveness of Posaconazole Versus Standard Azole Therapy in the Prevention of Invasive Fungal Infections among High-Risk Neutropenic Patients in the U.S.
Authors: O’Sullivan Amy K. , Pandya Ankur , Thompson David , Papadopoulos George , Weinstein Milton C. , Perfect John R. , Langston Amelia
Published: October 2019

In a recent clinical trial, posaconazole was found to be superior to standard azole therapy (i.e., fluconazole or itraconazole) in preventing both invasive fungal infections (IFIs) and in reducing overall mortality among high-risk neutropenic patients. We conducted a cost-effectiveness analysis based on trial results from a U.S. perspective. A decision-analytic model was developed to estimate the cost-effectiveness of antifungal prophylaxis among patients with acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) at high risk of developing an IFI due to chemotherapy-induced neutropenia. To extrapolate trial results to a lifetime horizon, the model was extended with one-month Markov cycles in which mortality risk is specific to the underlying disease as estimated from SEER data. Patients in the model were assumed to receive prophylaxis with posaconazole or standard azole therapy (fluconazole, 81%; itraconazole, 19%). The probabilities of experiencing an IFI, IFI-related death, and death from other causes over 100 days of follow-up were estimated from the trial data. Long-term mortality, drug costs, and IFI treatment costs were estimated using published sources. The model was used to estimate costs, IFIs avoided, life-years gained, and the incremental cost-effectiveness of posaconazole versus standard azole therapy (using 2006 dollars). Posaconazole is associated with fewer IFIs (0.05 vs. 0.11), increased life years (0.744 vs. 0.728), and (excluding costs of the underlying condition) slightly lower costs ($4,887 vs. $5,070) per patient relative to standard azole therapy over a lifetime horizon. One-way sensitivity analyses indicate that when model parameters are varied across reasonable ranges of their base-case values, the incremental cost-effectiveness ratio for posaconazole ranges from cost saving to $50,000 per life-year saved relative to standard azole therapy. A second-order probabilistic Monte Carlo sensitivity analysis was conducted to assess the effects of parameter uncertainty on the study findings, particularly as relates to treatment efficacy and the costs of an IFI. Results indicate that there is a 75% probability that posaconazole is cost saving versus standard azole therapy and a 90% probability that the incremental cost-effectiveness ratio for posaconazole is at or below the $50,000 per life year saved threshold. Posaconazole has been shown to be more effective than standard azole therapy (i.e., fluconazole or itraconazole) in preventing IFIs and reducing overall mortality in high-risk neutropenic patients.

Based on this analysis, we conclude that posaconazole is likely to be cost saving relative to standard azole therapy (i.e., fluconazole or itraconazole) in the prevention of IFIs among high-risk neutropenic patients.
Chemotherapy-Related Amenorrhea (CRA) among Premenopausal Patients Treated for Acute Leukemia.
Authors: Fanning Suzanne R. , Jin Tao , Hilden Joanne M. , Advani Anjali , Kalaycio Matt , Lichtin Alan E. , Sekeres Mikkael A. , Sobecks Ronald , Moore Halle C.F.
Published: October 2019

Background: Little is known about the late effects of treatment for acute leukemia on ovarian function. We sought to evaluate the rate of long-term chemotherapy-related amenorrhea (CRA) among premenopausal women treated for acute leukemia.

Methods: The Cleveland Clinic database of patients treated for acute leukemia between July 1994 and July 2005 was searched for patients aged 15–44 at diagnosis who were believed to be alive. Thirty of 69 identified patients were excluded due to active disease, on-going treatment or lost to follow-up. Questionnaires regarding menstrual and fertility history were mailed to the remaining 39 patients.

Results: Twenty-five patients responded to the questionnaire, 4 of whom were excluded due to lack of menses at the time of diagnosis (n=2), use of Depo-provera at time of diagnosis (n=1) or use of Depo-provera at time of f/u (n=1). The median age of the remaining 21 patients was 30 (range 15 to 44). Thirteen patients had AML and 8 had ALL. Nine of the 21 had undergone myeloablative transplant, 8 allogeneic and 1 autologous. Median f/u time from treatment was approximately 43 months (range 9 to 141). Long-term CRA occurred in 8/21 patients (38%). Only 2/12 patients (17%) who received standard-dose chemotherapy alone had persistent CRA while 6/9 (67%) of those undergoing transplant had persistent CRA (p=0.032, Fisher’s Exact test). The incidence of CRA increased with age: 0/3 patients under age 18, 1/4 patients age 18–25, and 7/14 patients age 26–44 at treatment remained amenorrheic (p=0.042, 1-sided Cochran-Armitage test). Only 2 patients reported attempts at fertility following treatment. One patient reported delivering three children, the other patient was amenorrheic and was undergoing fertility treatment.

Conclusions: These findings suggest that a substantial minority of young survivors of acute leukemia will experience premature ovarian failure. Increasing age at treatment and transplant are associated with a greater risk of long-term CRA.
Invasive Streptococcus Pneumoniae Infections in Pediatric Cancer Patients: High Morbidity and Mortality with Several Vaccine Failures.
Authors: Weber Lynn , Allen Charlet A. , Ackerman Patricia , Messinger Yoav
Published: October 2019

Invasive pneumococcal infections can be devastating in the setting of immune deficiency. These infections have been seen in pediatric oncology practices, but the outcome has not been reported. With the introduction of routine 7- valent pneumococcal conjugate vaccine (PCV7) the rate of pneumococcal infections dramatically decreased in the general pediatric population. It is unclear if a similar reduction in rate would be seen in pediatric oncology patients. A total of 44 pneumococcal infections occurred in 34 oncology patients at Childrens Hospital and Clinics of Minnesota over a 5-year period (5/1/2001 – 4/30/2006). Twenty-five episodes of invasive infection were identified in 24 patients, of which 4 (16.7%) required intensive care admissions and 2 of them died (8.3%). During this period 863 new malignancies were diagnosed, therefore our rate of invasive infection is estimated to be 28 per 1000 oncology patients. This is higher than the reported rate of 3.8 8.1 infections per 1000 stem cell transplantation patients. Fifteen patients (62%) with invasive infections were diagnosed with leukemia, of which 12 had acute lymphoblastic leukemia. The invasive infections occurred a median of 15.2 months (range 0–36) after diagnosis and the median patient age at time of infection was 5.6 years (range 1.5 - 14). The average length of hospitalization for patients was 8.3 days (range 0–38), with six patients receiving outpatient therapy alone. Pneumococcal serotypes were known in 21 of the 25 episodes of invasive pneumococcal infection and in 1 non-invasive infection. Of the 22 serotypes identified, 19 were covered by either PCV7 or the 23-valent pneumococcal polysaccharide vaccine (PS23). Eleven patients who were immunized with either PCV7 or PS23 later developed a pneumococcal strain that should have been covered by the immunization. Three patients who received immunization acquired a strain of streptococcus pneumoniae not included in either vaccine. Invasive pneumococcal infection is a potentially preventable complication with a high morbidity and mortality. Use of PCV7 or PS23 may not prevent the development of pneumococcal infection in pediatric oncology patients with vaccine-susceptible strains. It is unclear whether immunization before and during the immunocompromised period results in protective immunity against streptococcus pneumoniae.
Low Dose Liposomal Amphotericin B (L-AmB) as Prophylaxis of Invasive Fungal Infections (IFI) in Neutropenic Patients (pts): Is It Cost Effective?.
Authors: Penack Olaf , Martus Peter , Thiel Eckhard , Blau Igor W.
Published: October 2019

Background In a recently reported randomized trial (ASH meeting 2005, oral presentation #1310) low-dose intravenous L-AmB reduced the incidence of IFI (20.2% vs. 4.6%, p<0.001) in high risk pts with hematological malignancies and prolonged neutropenia. The purpose of the current study was to compare the pharmacoeconomics of L-AmB prophylaxis vs. no systemic antifungal prophylaxis.

Methods: Records of all randomized pts with acute leukemia were reviewed for dosage and duration of antimycotic and antibiotic treatment during hospital stay. Based on this data and current drug prices the mean costs of antimicrobial treatment (AT) per hospital stay were calculated.

Results Pt. characteristics: Randomized pts 132; eligible pts 100; arm A: 56 (L-AmB prophylaxis); arm B: 44 (no prophylaxis). Baseline characteristics were balanced for age (mean 55.8 years), underlying disease (81 AML, 19 ALL) and duration of neutropenia (mean 18.5 days). Endpoints: The costs for antifungal treatment (excluding prophylaxis) were 360 Euro in arm A vs. 2170 Euro in arm B (p<0.001). Expenditures for antifungal prophylaxis accounted for 630 Euro in arm A vs. 0 Euro in arm B. The costs of antibiotic treatment were lower in arm A compared to arm B (210 Euro vs. 670 Euro, p<0.001). The total costs for AT (including antifungal prophylaxis) per hospital stay were 1200 Euro in arm A vs. 2840 Euro in arm B (p=0.071).

Conclusion: Our results suggest that antifungal prophylaxis with low dose L-AmB in high risk patients with hematologic malignancies has the potential to reduce the incidence of IFI and may be a cost-saving strategy.
Inadvertent Intrathecal Administration of Vincristine.
Authors: Basetty Praveena , Buffie Charlie G. , Lagman Jennifer , Tigue Cara C. , Dandade Neal , Bennett Charles L.
Published: October 2019

Background: Vincristine is a vesicant drug which is normally given intravenously. Intrathecal administration of vincristine is a therapeutic misadventure, causing chemical leptomeningitis and focal ventriculitis. While 55 cases of intrathecal vincristine administration have been reported worldwide, only 32 cases have been documented in the literature, 13 have been reported to the FDA Med Watch, and many more cases are believed to be unreported. Of the documented cases, 84.3% resulted in death and 15.6% of those who survived had serious neurological consequences such as quadriplegia and paraplegia.

Methods: The Research on Adverse Events and Reports (RADAR) project conducted a review of literature published between 1968 and June 2006. Sources included Med Watch reports, published abstracts and journal articles, online newsletters, and letters from pharmacists.

Findings: The reports reviewed showed that intrathecal administration of vincristine occurred most often because of inadequate communication between pharmacy and medical staff (22 of 32 cases; 68.7%). In these cases, the pharmacy mistakenly delivered vincristine syringes together with syringes containing intrathecal medications and physicians or nurses wrongly administered vincristine intrathecally. Pharmacy error alone, such as the mislabeling of syringes, accounted for 6 of 32 cases of intrathecal administration of vincristine (18.7%) while physician/nurse error alone (failure to read syringe labeling or check physician’s orders) accounted for 4 of 32 cases (12.5%).

Conclusions: Since vincristine is lethal when given intrathecally, its administration should be executed with the precautionary measures employed with other potentially lethal substances, such as blood products. Carefully reviewing physician orders before drug administration and dispensing vincristine in syringes incompatible with spinal needles can also curb fatal error. Other preventive measures include properly labeling vincristine syringes for intravenous use only and diluting vincristine in intravenous mini-infusion bags.

Literature review of case reports since 1968 < 1985 1986–1990 1991–1995 1996–2000 2001–2005 Total USA/Canada 7 1 2 4 2 16 Europe 0 0 2 2 1 5 Australia 0 1 1 0 1 3 Asia 1 0 1 3 0 5 Total Cases 8 2 6 8 8 32 Deaths 8 1 4 6 8 27 (84.3%) Pharmacy/medical staff error 5 1 3 5 5 22 (68.7%) Pharmacy error 2 0 2 2 3 6 (18.7%) Physician/Nurse error 1 1 1 1 0 4 (12.5%)
Younger Patients with CLL/SLL Are Less Frequent and Have Favorable Survival in a Canadian Population Based Study: The Manitoba Cohort.
Authors: Banerji Versha , Demers Alain , Johnston James B. , Pitz Marshall W. , Nugent Zoanne , Morales Carmen , Mahmud Salah , Hewitt Donna , Gibson Spencer B. , Seftel Matthew D.
Published: October 2019

Background: Detailed population-based clinical characteristics and outcomes of chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL) are scarce. We have previously demonstrated in the province of Manitoba that by combining population-based sources of a cancer registry and a centralized flow cytometry database, the incidence of CLL/SLL is much higher than previously reported. We have now examined the clinical characteristics of this large and well defined patient group. We hypothesized that the clinical features of these patients (pts) may differ from previous studies where data was obtained from referral centers.

Methods: All pts from the Manitoba Cancer Registry with ICD codes 9 & 10 for CLL or SLL from 01/01/1998 to 12/31/2003 were identified. Pts from the flow cytometry database during this time period with a diagnosis of CLL/SLL were also identified. A retrospective electronic chart review was conducted. The two databases were compared and analyzed.

Results: 715 pts with CLL were identified. 358 pts were identified from the cancer registry alone, 136 pts by the flow cytometry database, and 221 pts in both datasets. Overall, the age-adjusted annual incidence rate of CLL/SLL in Manitoba was 10.5/105 (95% C.I. 9.4–12.7/105). Median age of all pts was 72yrs (19–101). Only 71 pts (9.9%) were aged <55 and 212 pts (29.6) were <65. The Male: Female ratio was identical in the age<55 and >55 categories (1.33). Median follow-up of living pts is 6.6 years (range 2.0–8.0). The Cox regression model was used to evaluate the significance of prognostic factors including age at diagnosis and gender. Older cases (>55 years) had significantly higher risk of dying (HR: 4.0, 95%CI: 1.23–13.1) than younger pts. Women had a slightly lower risk of dying (HR: 0.78, 95%CI: 0.40–1.50) than men. For the 136 pts for whom accurate Rai staging was available, estimated median survival has not been reached in stage 0 patients, while it was 7.2 years in stage I–II cases and 4.5 years in stage III–IV patients. Cause specific mortality and complete survival according to Rai stage for all pts will be presented at the meeting.

Conclusions: In this population-based CLL/SLL cohort, clinical presentation and outcomes appear to differ from previously reported studies. Specifically, (1) there are fewer younger pts, (2) the male: female ratio is similar amongst all ages, (3) older pts have a significantly poorer survival, (4) pts with advanced Rai stages appear to live longer than previously reported. This has important implications for treatment and counseling of pts, as well as for resource allocation for this common hematological malignancy.
Cost-Effectiveness of Rituximab Maintenance Treatment Versus Autologous Stem Cell Transplantation (ASCT) in Patients with Relapsed Follicular Lymphoma (FL).
Authors: Leppä Sirpa , Linna Miika , Nyman Heidi , Taimela Eeva
Published: October 2019

PURPOSE: High dose chemotherapy followed by ASCT is commonly used in responding patients with FL as consolidation treatment in first relapse. Recently, rituximab maintenance treatment has shown to improve both progression free (PFS) and overall survival (OS) in the same patient population. The objective of this analysis was to estimate the incremental cost-effectiveness of rituximab maintenance compared to ASCT in patients with FL in first relapse.

METHODS: Efficacy data for rituximab maintenance treatment was derived from the EORTC 20981 trial (van Oers et al, ASH 2005). FL patients (n=334) were randomized to observation or rituximab maintenance treatment in first relapse. Rituximab maintenance treatment consisted of eight infusions during two years. The reported PFS for R-CHOP induction followed by maintenance arm was 51.9 mo, in comparison to 23.1 mo for observation arm. Efficacy data on ASCT and immunochemotherapy were derived from local experience during 1994–2005. Twelve patients with relapsed FL received ASCT, and had median PFS of 34.1 mo. In comparison, fifty patients who received immunochemotherapy without neither ASCT nor rituximab maintenance had a PFS of 21.8 mo, which is comparable to the outcome of R-CHOP treated patients in the observation arm of the EORTC 20981 study. To estimate the incremental resources involved we included therapy associated costs, and visit costs during the first two years. Rituximab maintenance costs included eight infusion visits, in addition to drug costs. Costs for ASCT were based on real data of individual patients, collected from hospital’s accounting systems. These costs are also used as prices charged by Helsinki University Hospital (HUCH) in Finland. The costs included only direct medical costs for hospital services and were calculated in 2004 prices.

RESULTS: The cost of rituximab maintenance treatment was estimated to be approximately EUR 19.700. The actual cost of ASCT was approximately EUR 38.600. In terms of health benefits, rituximab maintenance seems to provide longer PFS after first relapse, with incremental difference of 17.8 mo, based on these early results reported. In the base case, therapy associated costs were lower in the rituximab maintenance treatment group. After sensitivity analysis without follow-up visit costs, this difference remained. Thus, rituximab maintenance treatment was the dominant choice in treating FL patients at first relapse, when compared to ASCT.

CONCLUSIONS: This analysis cloncludes that new treatment approaches may lead to improved PFS combined with cost savings in those FL patients where ASCT previously has been the preferred treatment option. The potential impact of these findings on the whole FL patient population will be discussed.
Experience of Respect and Pain Management among Adult Patients with Sickle Cell Disease during Vaso-Occlusive Crisis.
Authors: Beach Mary Catherine , Duggan Patrick , Lanzkron Sophie
Published: October 2019

BACKGROUND. Adults with sickle cell disease (SCD) have reported adversarial relationships with health professionals in qualitative studies, but there are no quantitative data. We sought to examine experiences of respect among patients with SCD seeking acute care for vaso-occlusive crisis (VOC), and to relate these experiences to quality of pain management.

METHODS. We surveyed 54 adult patients upon discharge from the Emergency Department (ED) at an urban academic medical center. We measured patient experience of respect using items from the Interpersonal Processes of Care Instrument and summed responses to form a ‘respect’ scale from 0–100 (alpha 0.89). We measured pain management quality by asking patients whether doctors and nurses brought them their pain medicines as soon as they needed them and changed their pain medicines if they were not working (‘all’ and ‘most’ of the time were considered favorable responses while ‘some’ or ‘none’ of the time were considered unfavorable).

RESULTS. Patients generally reported low levels of respect and poor pain management. A small proportion of patients reported (‘all of the time’) that doctors and nurses seemed to care about them as a person (19%), listened carefully to what they had to say (17%), and took their concerns seriously (13%). A substantial proportion reported (‘all, ‘most’ or ‘some of the time’) that their doctors and nurses had a negative attitude towards them (63%), made them feel inferior (74%), made them feel as if they weren’t welcome (65%) and behaved rudely towards them (50%). Only 34% of patients reported timely receipt of pain medication and 48% reported that ineffective medication was changed. Patient experience of respect and pain management quality were not significantly related to patient age, sex, or employment status; however patients seen more frequently in the ED reported less respect (mean respect scores 74.1, 62.7, and 54.6 for patients seen <5 times/year, 5–15 times/year, and >15 times per year respectively, p=0.04). Patients who experienced lower respect also reported poorer pain management quality. Compared to patients who reported timely receipt of and changes in ineffective medication, patients who reported delays in receipt and no change in ineffective medication had lower respect scores (mean 71.9 vs. 53.9, p=0.001 for timely vs. delayed; 65.6 vs. 53.7 for change vs. no change).

CONCLUSION. Interventions are needed to improve the experiences of adult patients with SCD who present to the ED with VOC. Further research is needed to determine the causes of poor experiences of respect and pain management, and to determine their further consequences.
Cost of Current Iron Chelation Infusion Therapy and Cost-Effectiveness of Once-Daily Oral Deferasirox in Transfusion-Dependent Thalassemia Patients in Canada.
Authors: Delea T.E. , El Ouagari K. , Sofrygin O.
Published: October 2019

Background: Deferasirox (Exjade®) is a recently approved once-daily oral chelator that has been shown to produce reductions in liver iron concentrations and serum ferritin similar to those with infusional deferoxamine (Desferal®), in patients with β-thalassemia major or sickle cell disease (SCD) and chronic iron overload from blood transfusions. The objective of this study was to estimate the cost of deferoxamine administration in Canada and evaluate the cost-effectiveness of deferasirox versus deferoxamine for chronic iron overload from blood transfusions from the Ontario provincial healthcare system.

Methods: Cost of chelation therapy with deferoxamine was estimated from five major treatment centers in Canada. Costs comprised the material used and the time spent by hospital pharmacists in preparing deferoxamine infusions. Cost-effectiveness of the new oral iron chelator, deferasirox, which could replace deferoxamine, was estimated using a Markov model. The model estimates and compares the total lifetime costs and quality-adjusted life years (QALYs) related to the use of deferasirox or deferoxamine in patients with β-thalassemia major at risk of chronic iron overload from blood transfusions. Dosages of deferasirox and deferoxamine used in the model were those that have been shown to be similarly effective in such patients. Compliance with deferoxamine was based on analyses of health-insurance claims data from transfusion-dependent thalassemia patients. Probabilities of complications of iron overload and death by compliance with chelation were estimated from published studies. Because data on compliance with deferasirox in typical clinical practice are unavailable, we used published data on compliance with the oral chelator deferiprone versus deferoxamine. Costs of deferasirox, deferoxamine, and drugs used in the treatment of complications of iron overload were based on publicly available data sources. Utilities were based on a study of patient preferences for oral versus infusional chelation therapy, as well as published literature and assumption. Future costs and QALYs were discounted at 5% annually. Costs were adjusted to 2004 Canadian dollars.

Results: Cost of yearly infusion therapy in Canada was estimated at $6,000 per patient, excluding deferoxamine drug cost. Cost-effectiveness of deferasirox compared to deferoxamine was estimated at $45,054 per QALY gained resulting mainly from a gain in 2.9 QALYs obtained at an expected lifetime cost of $130,058 per patient. Cost-effectiveness is sensitive to the estimated costs of deferoxamine and infusional therapy, as well as the quality of life benefit associated with oral versus infusional therapy, and is more favorable in younger patients.

Conclusion: In patients with transfusion-dependent β-thalassemia, the cost-effectiveness of deferasirox versus deferoxamine is within the range generally considered acceptable in Canada.
Screening for Iron Deficiency: Can We Continue To Avoid Ferritin?.
Authors: Montoya Maria E. , Van Delden Peter R. , Elghetany M. Tarek , Bessman J. David
Published: October 2019

Detection of iron deficiency remains poorly understood and costly due to inappropriate screening. Low ferritin is a definitive diagnosis of iron deficiency, but screening with ferritin is not allowed. Therefore surrogates in the blood count have been used to justify obtaining the serum ferritin. The purpose of this research was to analyze the role of Hemoglobin (Hgb), Mean Corpuscular Volume (MCV), and RBC Distribution Width (RDW) as surrogates in screening for iron deficiency. All 2,563 patients with serum ferritin levels gathered over 12 months were reviewed. The relative utility of Hgb, MCV, and RDW in screening for low ferritin levels was shown through multiple Receiver Operator Characteristic (ROC) curves. 264 patients had a ferritin less than 10 ng/ml and 210 between 11 to 20 ng/ml. Results indicate that when viewed independently MCV correlates most closely to low ferritin as seen in Figure 1. RDW and Hgb in both males and females demonstrate a weaker association though remains of value. Table1 lists the values at which the three screening tools were 95% and 100% sensitive for detecting ferritin levels of 10 ng/ml and below. In contrast the data indicate that for ferritin levels from 11 to 20 ng/ml all three screening variables have poor sensitivity and specificity. This is demonstrated clearly in Figure 2. The data suggest that the most severe iron deficiency (ferritin under 10 ng/ml) can be well predicted by abnormalities in the blood count; however less severe iron deficiency (ferritin 10 to 20 ng/ml) cannot be anticipated from the blood count. The blood count does not appear to be a practical alternative to ferritin for screening for iron deficiency.

Table 1: Sreening Variable Sensitivities* 100% Sensitivity 95% Sensitivity *values for ferritin less than 11 ng/ml MCV >98.2 >90.0 RDW <12.2 <13.1 Hgb Males >15.0 >13.7 Hgb Females >14.2 >12.6 Figure 1 Figure 1. Figure 2 Figure 2.
Long Term Follow-Up of Patients with Chronic Myeloid Leukemia Receiving BuCy2 as Preparation for Allotransplantation.
Authors: Copelan Edward A. , Dodds Anthony J. , Bolwell Brian J. , Crilley Pamela Ann , Elder Patrick , Pant Shubham , Kalaycio Matt , Sobecks Ronald , Topolsky David , Nivison-Smith Ian , Avalos Belinda R. , Szer Jeffrey
Published: October 2019

In 1992, we published the results of the first multi-institutional study of BuCy2 (busulfan 4mg/kg daily for four days and cyclophosphamide 60mg/kg on each of two days) preparation for allogeneic transplantation using related HLA-identical donors in chronic myeloid leukemia (CML). Median follow-up was 3 years. This report updates outcomes to July 1, 2006 for a total of 294 patients, including the original cohort, who underwent allogeneic transplantation with the BuCy2 regimen at 7 centers between March 1984 and December 1995. The median follow-up of surviving patients is 13 years. Two hundred patients underwent transplantation in chronic phase, 58 in accelerated phase and 36 in blastic phase. One hundred thirty two patients (45%) remain alive. Seventy-nine percent of patients surviving 3 years after transplantation are estimated survivors 13 years after transplantation. The estimated survivals at 3 and 13 years are 69% (95% CI: 57–81%) and 56% (42–70%) for chronic phase patients, 38% (14–62%) and 25% (1–49%) for accelerated phase patients, and 17% (0–41%) and 4% (0–16%) for those in blastic phase. Estimated relapse rates, according to stage of disease, are 6% (0–14%), 21% (1–49%), and 55% (7–100%) respectively at 3 years and 22% (6–38%), 42% (0–84%) and 74% (20–100%) respectively at 13 years. Of 51 patients who developed hematologic or persistent cytogenetic relapse, 28 relapsed within 3 years of transplantation and 23 (45%) relapsed more than 3 years from transplantation (longest: 15 years) Twenty-five of the 28 patients who relapsed within 3 years have died. Of the 23 who relapsed beyond 3 years, 7 have died. Death occurred more frequently (P<0.001) and the interval from relapse to death was shorter (P=0.02) for those who relapsed within 3 years. Of 162 patients who have died, 34 died beyond 3 years, most commonly from chronic GVHD (10), relapse (9), or new malignancies (6). Advanced stage was a risk factor for late failure (death or relapse beyond 3 years, P=0.003), as it was for early failure (P=0.001). Older age (P=0.03) and chronic GVHD (P=0.05) were also risk factors for late failure. For chronic phase patients, risk of late failure was not increased in those who underwent transplantation at longer intervals from diagnosis (P=0.5), in contrast to early failure (P=0.002). In conclusion, approximately four of five patients with CML who underwent allo-transplantation using BuCy2, and were alive 3 years following transplantation, are survivors at 13 years. Late relapse was associated with a significantly better outcome than early relapse. Late deaths occurred most frequently due to chronic GVHD, relapse or new malignancies.