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1.  Economics and Outcome After Hematopoietic Stem Cell Transplantation: A Retrospective Cohort Study 
EBioMedicine  2015;2(12):2101-2109.
Hematopoietic stem cell transplantation (HSCT) is a lifesaving expensive medical procedure. Hence, more transplants are performed in more affluent countries. The impact of economic factors on patient outcome is less defined. We analyzed retrospectively a defined cohort of 102,549 patients treated with an allogeneic (N = 37,542; 37%) or autologous (N = 65,007; 63%) HSCT. They were transplanted by one of 404 HSCT centers in 25 European countries between 1999 and 2006. We searched for associations between center-specific microeconomic or country-specific macroeconomic factors and outcome. Center patient-volume and center program-duration were significantly and systematically associated with improved survival after allogeneic HSCT (HR 0·87; 0·84–0·91 per 10 patients; p < 0·0001; HR 0·90;0·85–0·90 per 10 years; p < 0·001) and autologous HSCT (HR 0·91;0·87–0·96 per 10 patients; p < 0·001; HR 0·93;0·87–0·99 per 10 years; p = 0·02). The product of Health Care Expenditures by Gross National Income/capita was significantly associated in multivariate analysis with all endpoints (R2 = 18%; for relapse free survival) after allogeneic HSCT. Data indicate that country- and center-specific economic factors are associated with distinct, significant, systematic, and clinically relevant effects on survival after HSCT. They impact on center expertise in long-term disease and complication management. It is likely that these findings apply to other forms of complex treatments.
•Hematopoietic stem cell transplants (HSCTs) are expensive; economics plays a role on use and outcome.•102,549 patients treated with HSCT in 404 European centers between 1999 and 2006 were investigated.•Center program duration, patient volume, accreditation and country economics were associated with survival.•Effects were significant, clinically relevant but distinct for allogeneic and autologous HSCT.
Hematopoietic stem cell transplantation (HSCT) is lifesaving but expensive; it's more frequently used in richer countries. We asked whether economics impact on outcome. For 102,549 patients treated with an allogeneic or autologous HSCT in 404 European centers between 1999 and 2006 survival was significantly better in centers with longer program duration and a higher patient volume. Survival was better in economically advantaged countries. Data indicate distinct, significant, systematic, and clinically relevant effects on long-term disease and complication management by country- and center-specific economic factors. It is likely that these effects apply to other forms of complex treatments.
PMCID: PMC4703735  PMID: 26844291
Hematopoietic stem cell transplantation; Macroeconomics; Microeconomics; Center effect; Patient volume; Program duration; Outcome; Survival; GNI/cap; HCE/cap; HDI; Risk assessment
2.  The use of erythropoiesis-stimulating agents with ruxolitinib in patients with myelofibrosis in COMFORT-II: an open-label, phase 3 study assessing efficacy and safety of ruxolitinib versus best available therapy in the treatment of myelofibrosis 
Anemia is considered a negative prognostic risk factor for survival in patients with myelofibrosis. Most patients with myelofibrosis are anemic, and 35–54 % present with anemia at diagnosis. Ruxolitinib, a potent inhibitor of Janus kinase (JAK) 1 and JAK2, was associated with an overall survival benefit and improvements in splenomegaly and patient-reported outcomes in patients with myelofibrosis in the two phase 3 COMFORT studies. Consistent with the ruxolitinib mechanism of action, anemia was a frequently reported adverse event. In clinical practice, anemia is sometimes managed with erythropoiesis-stimulating agents (ESAs). This post hoc analysis evaluated the safety and efficacy of concomitant ruxolitinib and ESA administration in patients enrolled in COMFORT-II, an open-label, phase 3 study comparing the efficacy and safety of ruxolitinib with best available therapy for treatment of myelofibrosis. Patients were randomized (2:1) to receive ruxolitinib 15 or 20 mg twice daily or best available therapy. Spleen volume was assessed by magnetic resonance imaging or computed tomography scan.
Thirteen of 146 ruxolitinib-treated patients had concomitant ESA administration (+ESA). The median exposure to ruxolitinib was 114 weeks in the +ESA group and 111 weeks in the overall ruxolitinib arm; the median ruxolitinib dose intensity was 33 mg/day for each group. Six weeks before the first ESA administration, 10 of the 13 patients had grade 3/4 hemoglobin abnormalities. These had improved to grade 2 in 7 of the 13 patients by 6 weeks after the first ESA administration. The rate of packed red blood cell transfusions per month within 12 weeks before and after first ESA administration remained the same in 1 patient, decreased in 2 patients, and increased in 3 patients; 7 patients remained transfusion independent. Reductions in splenomegaly were observed in 69 % of evaluable patients (9/13) following first ESA administration.
Concomitant use of an ESA with ruxolitinib was well tolerated and did not affect the efficacy of ruxolitinib. Further investigations evaluating the effects of ESAs to alleviate anemia in ruxolitinib-treated patients are warranted ( identifier, NCT00934544; July 6, 2009).
PMCID: PMC4570722  PMID: 26380150
Myelofibrosis; Ruxolitinib; Anemia management; Erythropoiesis-stimulating agents; ESA
3.  Effect of a structured psycho-oncological screening and treatment model on mental health in cancer patients (STEPPED CARE): study protocol for a cluster randomized controlled trial 
Trials  2014;15:482.
High levels of emotional distress in cancer patients often goes unnoticed in daily clinical routine, resulting in severe undertreatment of mental health problems in this patient group. Screening tools can be used to increase case identification, however, screening alone does not necessarily translate into better mental health for the patient. Doctors play a key role in providing basic emotional support and transferring the patients in need of such specific support to mental health professionals. This study investigates whether a stepped care model, combining screening, doctor consultation and professional psycho-oncological service in a structured way, improves the emotional wellbeing of cancer patients.
This study is a cluster randomized trial with two parallel groups (intervention vs. care as usual), set in an academic hospital. Participants are cancer patients, a total of 1,000 at baseline. The intervention consists of stepped psychosocial care. Step one: screening for distress, step two: feedback of screening results to the doctor in charge of the patient and consultation with the patient, and step three: based on a shared patient-doctor decision, either transferal to the consultation liaison (CL) service or not. The outcome will be emotional well-being half a year after baseline, ascertained with the Hospital Anxiety and Depression Scale. Randomization will be done by the cluster randomization of wards.
Mental health problems not only cause emotional suffering but also direct and indirect costs. This calls for timely and adequate psychosocial support, especially as we know that such support is effective. However, not every cancer patient can and must be treated by a mental health professional. Allocating limited resources most sensibly and economically is of crucial importance for our healthcare system to ensure the best quality of care to as many patients as possible. It is the hope of the STEPPED CARE trial that this model is both effective and efficient, and that it can be implemented in other hospitals as well, if proven to be effective.
Trial registration
Clinical Trials Register ( identifier: NCT01859429 registration date 17 May 2013.
PMCID: PMC4295289  PMID: 25491069
Oncology; Randomized controlled trial; RCT; Cluster randomized trial; Psycho-oncology; Mental health; Screening; Healthcare
4.  Graft-Versus-Host Disease and Graft-Versus-Tumor Effects After Allogeneic Hematopoietic Cell Transplantation 
Journal of Clinical Oncology  2012;31(12):1530-1538.
We designed a minimal-intensity conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematologic malignancies unable to tolerate high-intensity regimens because of age, serious comorbidities, or previous high-dose HCT. The regimen allows the purest assessment of graft-versus-tumor (GVT) effects apart from conditioning and graft-versus-host disease (GVHD) not augmented by regimen-related toxicities.
Patients and Methods
Patients received low-dose total-body irradiation ± fludarabine before HCT from HLA-matched related (n = 611) or unrelated (n = 481) donors, followed by mycophenolate mofetil and a calcineurin inhibitor to aid engraftment and control GVHD. Median patient age was 56 years (range, 7 to 75 years). Forty-five percent of patients had comorbidity scores of ≥ 3. Median follow-up time was 5 years (range, 0.6 to 12.7 years).
Depending on disease risk, comorbidities, and GVHD, lasting remissions were seen in 45% to 75% of patients, and 5-year survival ranged from 25% to 60%. At 5 years, the nonrelapse mortality (NRM) rate was 24%, and the relapse mortality rate was 34.5%. Most NRM was a result of GVHD. The most significant factors associated with GVHD-associated NRM were serious comorbidities and grafts from unrelated donors. Most relapses occurred early while the immune system was compromised. GVT effects were comparable after unrelated and related grafts. Chronic GVHD, but not acute GVHD, further increased GVT effects. The potential benefit associated with chronic GVHD was outweighed by increased NRM.
Allogeneic HCT relying on GVT effects is feasible and results in cures of an appreciable number of malignancies. Improved results could come from methods that control progression of malignancy early after HCT and effectively prevent GVHD.
PMCID: PMC3625710  PMID: 23478054
5.  Comparison of Allogeneic Stem Cell Transplantation and Non-Transplant Approaches in Elderly Patients with Advanced Myelodysplastic Syndrome: Optimal Statistical Approaches and a Critical Appraisal of Clinical Results Using Non-Randomized Data 
PLoS ONE  2013;8(10):e74368.
Allogeneic stem cell transplantation (ASCT) from related or unrelated donors may cure patients with myelodysplastic syndromes (MDS), a heterogeneous group of clonal stem cell disorders. We analysed 384 elderly patients (55-69 years) with advanced MDS who received either ASCT (n=247) and were reported to The European Group for Blood and Marrow Transplantation (EBMT) or a non –transplant approach (n=137) reported to the Düsseldorf registry. Besides an attempt to answer the question of „comparison“, the purpose of this work is to explain the difficulties in comparing a non-transplant with a transplant cohort, when death before transplant is likely but unknown and the selection of patients for transplant is based on assumptions. It shows which methods are almost always biased and that even the most sophisticated approaches crucially rely on clinical assumptions. Using the most appropriate model for our data, we derive an overall univariate non-significant survival disadvantage for the transplant cohort (HR: 1.29, p = 0.11). We show that such an “average” hazard ratio is however misleading due to non-proportionality of the hazards reflecting early treatment related mortality, the occurring of which is logically correlated with the interval between diagnosis and transplant creating a disproportional drop in the (reconstructed) survival curve of the transplanted patients. Also in multivariate analysis (correcting for age > 60 (HR: 1.4, p = 0.02) and abnormal cytogenetics (HR: 1.46, p = 0.01)), transplantation seems to be worse (HR: 1.39, p = 0.05) but only in the (incorrect but commonly applied) model without time varying covariates. The long term (time depending) hazard ratio is shown to be virtually 1 and overall survival is virtually identical in both groups. Nonetheless no conclusion can be reached from a clinical point of view without assumptions which are by their very nature untestable unless all patients would be followed from diagnosis.
PMCID: PMC3792099  PMID: 24116002
6.  The cell fate determinant Llgl1 influences HSC fitness and prognosis in AML 
Inactivation of Llgl1 enhances HSC self-renewal and fitness and is associated with unfavorable outcome in human AML.
A unique characteristic of hematopoietic stem cells (HSCs) is the ability to self-renew. Several genes and signaling pathways control the fine balance between self-renewal and differentiation in HSCs and potentially also in leukemia stem cells. Recently, studies have shed light on developmental molecules and evolutionarily conserved signals as regulators of stem cells in hematopoiesis and leukemia. In this study, we provide evidence that the cell fate determinant Llgl1 (lethal giant larvae homolog 1) plays an important role in regulation of HSCs. Loss of Llgl1 leads to an increase in HSC numbers that show increased repopulation capacity and competitive advantage after transplantation. This advantage increases upon serial transplantation or when stress is applied to HSCs. Llgl1−/− HSCs show increased cycling but neither exhaust nor induce leukemia in recipient mice. Llgl1 inactivation is associated with transcriptional repression of transcription factors such as KLF4 (Krüppel-like factor 4) and EGR1 (early-growth-response 1) that are known inhibitors of HSC self-renewal. Decreased Llgl1 expression in human acute myeloid leukemia (AML) cells is associated with inferior patient survival. Thus, inactivation of Llgl1 enhances HSC self-renewal and fitness and is associated with unfavorable outcome in human AML.
PMCID: PMC3549713  PMID: 23277453
7.  Pretreatment long interspersed element (LINE)-1 methylation levels, not early hypomethylation under treatment, predict hematological response to azacitidine in elderly patients with acute myeloid leukemia 
OncoTargets and therapy  2013;6:741-748.
Epigenetic modulations, including changes in DNA cytosine methylation, are implicated in the pathogenesis and progression of acute myeloid leukemia (AML). Azacitidine is a hypomethylating agent that is incorporated into RNA as well as DNA. Thus, there is a rationale to its use in patients with AML. We determined whether baseline and/or early changes in the methylation of long interspersed element (LINE)-1 or CDH13 correlate with bone marrow blast clearance, hematological response, or survival in patients with AML treated with azacitidine.
An open label, phase I/II trial was performed in 40 AML patients (median bone marrow blast count was 42%) unfit for intensive chemotherapy treated with azacitidine 75 mg/m2/day subcutaneously for 5 days every 4 weeks. Bone marrow mononuclear cell samples were taken on day 0 (pretreatment) and day 15 during the first treatment cycle; LINE-1 and CDH13 methylation levels were quantified by methylation-specific, semiquantitative, real-time polymerase chain reaction.
Treatment with azacitidine significantly reduced LINE-1 but not CDH13 methylation levels over the first cycle (P < 0.0001). Absolute LINE-1 methylation levels tended to be lower on day 0 (P = 0.06) and day 15 of cycle 1 (P = 0.03) in patients who went on to achieve subsequent complete remission, partial remission or hematological improvement versus patients with stable disease. However, the decrease in LINE-1 methylation over the first treatment cycle did not correlate with subsequent response (P = 0.31). Baseline methylation levels of LINE-1 or CDH13 did not correlate with disease-related prognostic factors, including cytogenetic risk, relapsed/refractory AML, or presence of NPM1 or FLT3 mutations. No correlation was observed between LINE-1 or CDH13 methylation levels and overall survival.
Analysis of baseline LINE-1 methylation levels may help identify elderly AML patients who are most likely to respond to azacitidine therapy.
PMCID: PMC3699298  PMID: 23836986
DNA methylation; acute myeloid leukemia; azacitidine; clinical response; CDH13; LINE-1 methylation
8.  Kinetics of iron removal by phlebotomy in patients with iron overload after allogeneic hematopoietic cell transplantation 
Excess body iron could persist for years after allogeneic hematopoietic cell transplantation (HCT) with possible deleterious sequels. An iron depletive therapy with phlebotomy seems rational. Kinetics of iron removal by phlebotomy without erythropoietin support in non-thalassemic adult patients with iron overload after HCT and the impact of pre- and post-HCT hemochromatosis (HFE) genotype on iron mobilization were investigated. Patients and methods: Phlebotomy was initiated in 61 recipients of allografts due to hematologic malignancies (median age 48 years) after a median of 18 months. The prephlebotomy median serum ferritin (SF) was 1697ng/ml and the median number of blood transfusions 28 units. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST), alkaline phosphates (AP), and bilirubin were elevated in 55.7%, 64% and 11.5% patients respectively. HFE-genotype was elucidated by polymerase chain reaction using hybridization probes and melting curve analysis. Results: Phlebotomy was well-tolerated irrespective of age or conditioning. A negative iron balance in 80% of patients (median SF 1086 ng/ml) and a rise in hemoglobin were observed (p<0.0001). Higher transfusional burden and SF were associated with a greater iron mobilization per session (p=0.02). In 58% of patients, a plateau after an initial steady decline in SF was followed by a second decline under further phlebotomy. The improvement in ALT (p=0.002), AST (p=0.03), AP (p=0.01), and bilirubin (p<0.0001) did not correlate with the decline in SF. Mutant HFE-gene variants were detected in 14/55 (25%) pre-HCT and 22/55 (40%) patients post-HCT. Overall, dissimilar pre- and posttransplantational HFE-genotypes were detected in 20/55 (40%) patients. Posttransplantational mutant HFE variants correlated with a slower decline in SF (p=0.007). Conclusions: Phlebotomy is a convenient therapy of iron overload in survivors of HCT. A negative iron balance and a rise in hemoglobin were observed in the majority of patients. Liver dysfunction improved irrespective of SF reduction suggesting a probable rapid decline of the deleterious labile plasma iron. In recipients of grafts with mutant HFE variants a “mixed chimerism” of HFE in body tissues might be created with a change in the set point for iron regulation. The transient plateau in SF after an initial decline might reflect iron mobilization from various tissues.
PMCID: PMC3512175  PMID: 23226624
Iron overload; ferritin; phlebotomy; allogeneic HCT
9.  Safety and efficacy of defibrotide for the treatment of severe hepatic veno-occlusive disease 
Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome, is a potentially life-threatening complication of chemotherapeutic conditioning used in preparation for hematopoietic stem-cell transplantation (SCT). VOD may occur in up to 62% of patients undergoing SCT, with onset generally within the first month after SCT. In severe cases, 100-day mortality is in excess of 80%. Current management consists of best supportive care, with no agents to date approved for treatment in the USA or the EU. Defibrotide, a polydisperse oligonucleotide, has been shown in phase II and III trials to improve complete response and survival in patients undergoing SCT with severe VOD. This article reviews our current understanding of VOD, and examines recent clinical findings on defibrotide for the treatment and prophylaxis of VOD.
PMCID: PMC3627330  PMID: 23606935
defibrotide; sinusoidal obstruction syndrome; veno-occlusive disease
10.  Special Issues Related to Hematopoietic Stem Cell Transplantation in the Eastern Mediterranean Region and the First Regional Activity Report 
Bone Marrow Transplantation  2008;43(1):1-12.
Although several centers are now performing allogeneic HSCT in the Eastern Mediterranean (EM) region, the availability is still limited. Special issues including compatible donor availability and potential for alternate donor programs are discussed. In comparison to Europe & North America, differences in pattern of diseases and pre-HSCT general status particularly for patients with BM failure are described. Other differences including high seropositivity for CMV, Hepatitis B and C infection and specific observations about GVHD with its relation to genetically homogeneous community are also discussed.
We report that a total of 17 HSCT programs (performing 5 or more HSCTs annually) exist in 9 countries of the EM region. Only 6 programs are currently reporting to EBMT or IBMTR. A total of 7617 HSCTs have been performed by these programs including 5701 allogeneic HSCTs. Due to low HSCT team density (1.5583 teams/10 million inhabitants vs. 14.4333 in Europe) and very low HSCT team distribution (0.2729 teams/10,000 sq km area vs. <1 to 6 teams in Europe). GNI/capita had no clear association with low HSCT activity; however improvement in infrastructure & formation of EM regional HSCT registry are needed.
PMCID: PMC3351791  PMID: 19043456
11.  Long-Term Outcomes Among Older Patients Following Nonmyeloablative Conditioning and Allogeneic Hematopoietic Cell Transplantation for Advanced Hematologic Malignancies 
A minimally toxic nonmyeloablative regimen was developed for allogeneic hematopoietic cell transplantation (HCT) to treat patients with advanced hematologic malignancies who are older or have comorbidities.
To describe outcomes of patients ≥ 60 years.
Design, Setting, and Participants
From 1998 to 2008, 372 patients, 60–75 years old were enrolled in prospective clinical HCT trials at 18 collaborating institutions using conditioning with low-dose total body irradiation alone or combined with fludarabine 90 mg/m2 before related (n=184) or unrelated (n=188) donor transplants. Post-grafting immunosuppression included mycophenolate mofetil and a calcineurin inhibitor.
Main Outcome Measures
Overall and progression-free survivals were estimated by Kaplan-Meier method. Cumulative incidence estimates were calculated for acute and chronic GVHD, toxicities, achievement of full donor chimerism, complete remission, relapse, and non-relapse mortality. Hazard ratios (HR) were estimated from Cox regression models.
Overall, 5-year cumulative incidences of non-relapse mortality and relapse were 27% (95% CI, 22%–32%) and 41% (95% CI, 36%–46%), respectively, leading to overall and progression-free 5-year survivals of 35% (95% CI, 30%–40%) and 32% (95% CI, 27%–37%), respectively. These outcomes were not statistically significantly different when stratified by age groups. Furthermore, increasing age was not associated with increases in acute or chronic graft-versus-host disease (GVHD) or organ toxicities. In multivariate models, HCT-CI scores of 1–2 [HR, 1.58 (95% CI,1.08–2.31)] and ≥3 [HR, 1.97 (95% CI,1.38–2.80)] were associated with worse survival compared to HCT-CI score of 0 (overall P = 0.003). Similarly, standard relapse risk [HR, 1.67 (95% CI, 1.10–2.54)] and high relapse risk [HR, 2.22 (95% CI, 1.43–3.43)] were associated with worse survival compared to low relapse risk (overall P = 0.0008).
Among patients aged 60–75 years and treated with nonmyeloablative allogeneic HCT, 5-year overall and progression-free survivals were 35% (95% CI, 30%–40%) and 32% (95% CI, 27%–37%), respectively.
PMCID: PMC3217787  PMID: 22045765
Marrow transplantation; hematopoietic cell transplantation; age; comorbidities; toxicities; infections; performance status; graft-versus-host disease; withdrawal of immunosuppression; mortality; survival; comparative outcomes research
12.  Hematopoietic stem cell transplantation A Global Perspective 
Hematopoietic stem cell transplantation (HSCT) requires significant infrastructure. Little is known on its use and the factors associated with it on a global level.
To determine current use of HSCT, to assess differences in its application and to explore associations of macroeconomic factors with transplant rates on a global level.
Structured worldwide collection of numbers of allogeneic and autologous HSCT by main indication, donor type and stem cell source for the year 2006.
Worldwide Network for Blood and Marrow Transplantation (WBMT), a global non-profit umbrella organization for clinical HSCT.
All patients with an allogeneic or autologous HSCT for any indication transplanted in 2006 within any of the participating countries.
Main Outcome measures
Transplant rates (number of HSCT per 10 million inhabitants) by indication, donor type and country; description of main differences in HSCT use; macroeconomic factors of reporting countries associated with transplant rates.
There were 50’417 first HSCT, 21’516 allogeneic (43%), 28’901 autologous (57%) reported from 1’327 centers in 71 countries for leukemia (17’049 (34%; 89% allogeneic)), lymphoma (27’492 (54%; 87% autologous)), solid tumors (2’925 (6%, 95% autologous)), non-malignant disorder (2’593 (5%; 92% allogeneic)) or, “others” 358 (1%). Use of allogeneic or autologous HSCT, use of unrelated or family donors for allogeneic HSCT and proportions of disease indications varied significantly between countries and continental regions. In linear regression analyses, Government Health Care Expenditures (r2 = 77.33), team density (r2 =76.28), Human Development Index (r2 = 74.36) and Gross National Income /Capita (r2 = 74.04) showed the highest association with transplant rates.
HSCT is an accepted therapy today with different use and needs worldwide. Availability of resources, Governmental support and, access for patients to a team were identified as key factors for higher transplant rates.
PMCID: PMC3219875  PMID: 20424252
Hematopoietic stem cell transplantation; Global perspective; transplant rates; leukemia; lymphoma; solid tumors; non-malignant disorders; Gross National Income per capita; Human Development Index
13.  Allogeneic Haematopoietic Cell Transplantation after Nonmyeloablative Conditioning in Patients with T-Cell and Natural Killer-Cell Lymphomas 
British journal of haematology  2010;150(2):170-178.
Patients with T-cell (TCL) and natural killer-cell lymphomas (NKCL) have poor outcomes. This study examined the role of allogeneic haematopoietic cell transplantation (HCT) after non-myeloablative conditioning in this setting. Seventeen patients with TCL or NKCL, including three patients in first complete remission, received allogeneic HCT after 2 Gy total-body irradiation and fludarabine. The median age was 57 (range, 18–73) years. The median number of prior therapies was 3 (range, 1–7), six patients (35%) had failed prior autologous HCT, and five patients (29%) had refractory disease at the time of allograft. Postgrafting immunosuppression was provided with mycophenolate mofetil with cyclosporine or tacrolimus. After a median follow-up of 3.3 (range, 0.3–8.0) years among surviving patients, the estimated probabilities of 3-year overall and progression-free survival were 59% and 53%, respectively, while the estimated probabilities of non-relapse mortality and relapse at three years were 19% and 26%, respectively. Sixty-five percent of patients developed grades 2–4 acute graft-versus-host disease and 53% of patients developed chronic graft-versus-host disease. Allogeneic HCT after non-myeloablative conditioning is a promising salvage option for selected patients TCL and NKCL. These results suggest that graft-versus-T-cell lymphoma activity is responsible for long-term disease control.
PMCID: PMC2995443  PMID: 20507311
14.  Highly Elevated Serum Hepcidin in Patients with Acute Myeloid Leukemia prior to and after Allogeneic Hematopoietic Cell Transplantation: Does This Protect from Excessive Parenchymal Iron Loading? 
Advances in Hematology  2011;2011:491058.
Hepcidin is upregulated by inflammation and iron. Inherited (HFE genotype) and treatment-related factors (blood units (BU), Iron overload) affecting hepcidin (measured by C-ELISA) were studied in 42 consecutive patients with AML prior to and after allogeneic hematopoietic cell transplantation (HCT). Results. Elevated serum ferritin pre- and post-HCT was present in all patients. Median hepcidin pre- and post-HCT of 358 and 398 ng/mL, respectively, were elevated compared to controls (median 52 ng/mL) (P < .0001). Liver and renal function, prior chemotherapies, and conditioning had no impact on hepcidin. Despite higher total BU after HCT compared to pretransplantation (P < .0005), pre- and posttransplant ferritin and hepcidin were similar. BU influenced ferritin (P = .001) and hepcidin (P = .001). No correlation of pre- or posttransplant hepcidin with pretransplant ferritin was found. HFE genotype did not influence hepcidin. Conclusions. Hepcidin is elevated in AML patients pre- and post-HCT due to transfusional iron-loading suggesting that hepcidin synthesis remains intact despite chemotherapy and HCT.
PMCID: PMC3112503  PMID: 21687645
15.  Voriconazole Pharmacokinetics and Safety in Immunocompromised Children Compared to Adult Patients ▿  
The aim of this study was to investigate the pharmacokinetics and safety of voriconazole after intravenous (i.v.) administration in immunocompromised children (2 to 11 years old) and adults (20 to 60 years old) who required treatment for the prevention or therapy of systemic fungal infections. Nine pediatric patients were treated with a dose of 7 mg/kg i.v. every 12 h for a period of 10 days. Three children and 12 adults received two loading doses of 6 mg/kg i.v. every 12 h, followed by a maintenance dose of 5 mg/kg (children) or 4 mg/kg (adults) twice a day during the entire study period. Trough voriconazole levels in blood over 10 days of therapy and regular voriconazole levels in blood for up to 12 h postdose on day 3 were examined. Wide intra- and interindividual variations in plasma voriconazole levels were noted in each dose group and were most pronounced in the children receiving the 7-mg/kg dose. Five (56%) of them frequently had trough voriconazole levels in plasma below 1 μg/ml or above 6 μg/ml. The recommended dose of 7 mg/kg i.v. in children provides exposure (area under the concentration-time curve) comparable to that observed in adults receiving 4 mg/kg i.v. The children had significantly higher Cmax values; other pharmacokinetic parameters were not significantly different from those of adults. Voriconazole exhibits nonlinear pharmacokinetics in the majority of children. Voriconazole therapy was safe and well tolerated in pediatric and adult patients. The European Medicines Agency-approved i.v. dose of 7 mg/kg can be recommended for children aged 2 to <12 years.
PMCID: PMC2916341  PMID: 20547816
16.  Hepatic Veno-Occlusive Disease following Stem Cell Transplantation: Incidence, Clinical Course, and Outcome 
The occurrence of hepatic veno-occlusive disease (VOD) has been reported in up to 60% of patients following stem cell transplantation (SCT), with incidence varying widely between studies depending on the type of transplant, conditioning regimen, and criteria used to make the diagnosis. Severe VOD is characterized by high mortality and progression to multiorgan failure (MOF); however, there is no consensus on how to evaluate severity. This review and analysis of published reports attempts to clarify these issues by calculating the overall mean incidence of VOD and mortality from severe VOD, examining the effect of changes in SCT practice on the incidence of VOD over time, and discussing the methods used to evaluate severity. Across 135 studies performed between 1979 and October 2007, the overall mean incidence of VOD was 13.7% (95% confidence interval [CI] = 13.3%–14.1%). The mean incidence of VOD was significantly lower between 1979–1994 than between 1994–2007 (11.5% [95% CI, 10.9%–12.1%] vs 14.6% [95% CI, 14.0%–15.2%]; P < .05). The mortality rate from severe VOD was 84.3% (95% CI, 79.6%–88.9%); most of these patients had MOF, which also was the most frequent cause of death. Thus, VOD is less common than early reports suggested, but the current incidence appears to be relatively stable despite recent advances in SCT, including the advent of reduced-intensity conditioning. The evolution of MOF in the setting of VOD after SCT can be considered a reliable indication of severity and a predictor of poor outcome.
PMCID: PMC3018714  PMID: 19766729
Veno-occlusive disease; Stem cell transplantation; Incidence; Outcome; Severity; Multiorgan failure
17.  EBV-associated post-transplantation B-cell lymphoproliferative disorder following allogenic stem cell transplantation for acute lymphoblastic leukaemia: tumor regression after reduction of immunosuppression - a case report 
Diagnostic Pathology  2010;5:21.
Epstein-Barr virus (EBV)-associated B-cell post-transplantation lymphoproliferative disorder (PTLD) is a severe complication following stem cell transplantation. This is believed to occur as a result of iatrogenic immunosuppression leading to a relaxation of T-cell control of EBV infection and thus allowing viral reactivation and proliferation of EBV-infected B-lymphocytes. In support of this notion, reduction of immunosuppressive therapy may lead to regression of PTLD.
We present a case of an 18-year-old male developing a monomorphic B-cell PTLD 2 months after receiving an allogenic stem cell transplant for acute lymphoblastic leukemia. Reduction of immunosuppressive therapy led to regression of lymphadenopathy. Nevertheless, the patient died 3 months afterwards due to extensive graft-vs.-host-disease and sepsis. As a diagnostic lymph node biopsy was performed only after reduction of immunosuppressive therapy, we are able to study the histopathological changes characterizing PTLD regression. We observed extensive apoptosis of blast cells, accompanied by an abundant infiltrate comprising predominantly CD8-positive, Granzyme B-positive T-cells. This observation supports the idea that regression of PTLD is mediated by cytotoxic T-cells and is in keeping with the observation that T-cell depletion, represents a major risk factor for the development of PTLD.
PMCID: PMC2853499  PMID: 20356360
18.  Five-Year Follow-Up of Patients With Advanced Chronic Lymphocytic Leukemia Treated With Allogeneic Hematopoietic Cell Transplantation After Nonmyeloablative Conditioning 
Journal of Clinical Oncology  2008;26(30):4912-4920.
We reported encouraging early results of allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning in 64 patients who had advanced chronic lymphocytic leukemia (CLL). Here, we have extended the follow-up to a median of 5 years and have included data on an additional 18 patients.
Patients and Methods
Eighty-two patients, age 42 to 72 years, who had fludarabine-refractory CLL were conditioned with 2 Gy total-body irradiation alone or combined with fludarabine followed by HCT from related (n = 52) or unrelated (n = 30) donors.
Complete remission (CR) and partial remission were achieved in 55% and 15% of patients, respectively. Higher CR rates were noted after unrelated HCT (67% v 48%). The 5-year incidences of nonrelapse mortality (NRM), progression/relapse, overall survival, and progression-free survival were 23%, 38%, 50%, and 39%, respectively. Among 25 patients initially reported in CR, 8% relapsed and 8% died as a result of NRM, whereas 84% have remained alive and in CR. Among 14 responding patients who were tested and who had molecular eradication of their disease, two died as a result of NRM, two relapsed, and 10 have remained negative. At 5 years, 76% of living patients were entirely well, whereas 24% continued to receive immunosuppression for chronic graft-versus-host disease; the median performance status in each group was 100% and 90%, respectively. Lymphadenopathy ≥ 5 cm, but not cytogenetic abnormalities at HCT, predicted relapse. In a risk-stratification model, patients who had lymphadenopathy less than 5 cm and no comorbidities had a 5-year OS of 71%.
Nonmyeloablative HCT resulted in a median survival of 5 years for patients who had fludarabine-refractory CLL with sustained remissions and in the continued resolution of chronic graft-versus-host disease in surviving patients.
PMCID: PMC2652085  PMID: 18794548
19.  Comparison of Outcomes of HLA-Matched Related, Unrelated, or HLA-Haploidentical Related Hematopoietic Cell Transplantation following Nonmyeloablative Conditioning for Relapsed or Refractory Hodgkin Lymphoma 
We compared the outcome of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) for patients with relapsed or refractory Hodgkin lymphoma (HL) based on donor cell source. Ninety patients with HL were treated with nonmyeloablative conditioning followed by HCT from HLA-matched related, n = 38, unrelated, n = 24, or HLA-haploidentical related, n = 28 donors. Patients were heavily pretreated with a median of 5 regimens and most patients had failed autologous HCT (92%) and local radiation therapy (83%). With a median follow-up of 25 months, 2-year overall survivals, progression-free survivals (OS)/(PFS), and incidences of relapsed/progressive disease were 53%, 23%, and 56% (HLA-matched related), 58%, 29%, and 63% (unrelated), and 58%, 51%, and 40% (HLA-haploidentical related), respectively. Nonrelapse mortality (NRM) was significantly lower for HLA-haploidentical related (P =.02) recipients compared to HLA-matched related recipients. There were also significantly decreased risks of relapse for HLA-haploidentical related recipients compared to HLA-matched related (P = .01) and unrelated (P = .03) recipients. The incidences of acute grades III–IV and extensive chronic graft-versus-host disease (aGVHD, cGVHD) were 16%/50% (HLA-matched related), 8%/63% (unrelated), and 11%/35% (HLA-haploidentical related). These data suggested that salvage allogeneic HCTusing nonmyeloablative conditioning provided antitumor activity in patients with advanced HL; however, disease relapse/progression continued to be major problems. Importantly, alternative donor stem cell sources are a viable option.
PMCID: PMC2647369  PMID: 18940683
Hodgkin lymphoma; Hematopoietic cell transplantation; Nonmyeloablative
20.  Nonmyeloablative Unrelated Donor Hematopoietic Cell Transplantation for the Treatment of Patients with Poor-Risk, Relapsed or Refractory Multiple Myeloma 
The purpose of this study was to determine long-term outcome of unrelated donor nonmyeloablative hematopoietic cell transplantation in patients with poor-risk multiple myeloma. Twenty-four patients were enrolled. Seventeen patients (71%) had chemotherapy-refractory disease and 14 patients (58%) had disease relapse or progression after prior autologous transplantation. Thirteen patients underwent planned autologous transplantation followed 43–135 days later with unrelated transplantation, while 11 proceeded directly to unrelated transplantation. All 24 patients were treated with fludarabine (90 mg/m2) and 2 Gray total body irradiation and human leukocyte antigen (HLA)-matched unrelated peripheral blood stem cell transplantation. Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. The median follow-up was 3 years after allografting. One patient experienced non-fatal graft rejection. The incidences of acute grades II, III and chronic graft-versus-host disease were 54%, 13% and 75%, respectively. The 3-year non-relapse mortality was 21%. Complete responses were observed in 10 patients (42%) and partial responses in 4 (17%). At 3 years, overall and progression-free survival rates were 61% and 33%, respectively. Patients receiving tandem autologous-unrelated transplantation had superior overall and progression-free survivals, 77% and 51%, compared to patients proceeding directly to unrelated donor transplantation, 44% and 11%, respectively (progression-free survival p-value, 0.03). In summary, for patients with poor-risk, relapsed or refractory multiple myeloma, cytoreductive autologous transplantation followed with nonmyeloablative conditioning and unrelated hematopoietic cell transplantation is effective treatment with low non-relapse mortality, high complete remission rates and prolonged disease-free survival.
PMCID: PMC1950939  PMID: 17287157
Multiple myeloma; nonmyeloablative conditioning; allogeneic hematopoietic cell transplantation; unrelated donor; graft-versus-tumor effects; chronic graft-versus-host disease; peripheral blood stem cell transplantation
21.  Biosimilar agents in oncology/haematology: from approval to practice 
European Journal of Haematology  2011;86(4):277-288.
The regulation of biosimilars is a process that is still developing. In Europe, guidance regarding the approval and use of biosimilars has evolved with the products under consideration. It is now more than 3 years since the first biosimilar agents in oncology support, erythropoiesis-stimulating agents, were approved in the EU. More recently, biosimilar granulocyte colony-stimulating factors have received marketing approval in Europe. This review considers general issues surrounding the introduction of biosimilars and highlights current specific issues pertinent to their use in clinical practice in oncology. Information on marketing approval, extrapolation, labelling, substitution, immunogenicity and traceability of each biosimilar product is important, especially in oncology where patients are treated in repeated therapy courses, often with complicated protocols, and where biosimilars are not used as a unique therapy for replacement of e.g. growth hormone or insulin. While future developments in the regulation of biosimilars will need to address multiple issues, in the interim physicians should remain aware of the inherent differences between biosimilar and innovator products.
PMCID: PMC3085072  PMID: 21175852
Biosimilars; granulocyte colony-stimulating factor; biologics; substitution; traceability; extrapolation; international non-proprietary names

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