Publications by authors named "Kristina Carlson"

39 Publications

Autologous haematopoietic stem cell transplantation compared with alemtuzumab for relapsing-remitting multiple sclerosis: an observational study.

J Neurol Neurosurg Psychiatry 2021 02 26;92(2):189-194. Epub 2020 Oct 26.

Department of Neuroscience, Uppsala University, Uppsala, Sweden

Objective: To compare outcomes after treatment with autologous haematopoietic stem cell transplantation (AHSCT) and alemtuzumab (ALZ) in patients with relapsing-remitting multiple sclerosis.

Methods: Patients treated with AHSCT (n=69) received a conditioning regimen of cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulinerG (6.0 mg/kg). Patients treated with ALZ (n=75) received a dose of 60 mg over 5 days, a repeated dose of 36 mg over 3 days after 1 year and then as needed. Follow-up visits with assessment of the expanded disability status scale score, adverse events and MR investigations were made at least yearly.

Results: The Kaplan-Meier estimates of the primary outcome measure 'no evidence of disease activity' was 88% for AHSCT and 37% for ALZ at 3 years, p<0.0001. The secondary endpoint of annualised relapse rate was 0.04 for AHSCT and 0.1 for ALZ, p=0.03. At last follow-up, the proportions of patients who improved, were stable or worsened were 57%/41%/1% (AHSCT) and 45%/43%/12% (ALZ), p=0.06 Adverse events grade three or higher were present in 48/69 patients treated with AHSCT and 0/75 treated with ALZ in the first 100 days after treatment initiation. The most common long-term adverse event was thyroid disease with Kaplan-Meier estimates at 3 years of 21% for AHSCT and 46% for ALZ, p=0.005.

Conclusions: In this observational cohort study, treatment with AHSCT was associated with a higher likelihood of maintaining 'no evidence of disease activity'. Adverse events were more frequent with AHSCT in the first 100 days, but thereafter more common in patients treated with ALZ.
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http://dx.doi.org/10.1136/jnnp-2020-323992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841472PMC
February 2021

Diagnostic Accuracy of [C]PIB Positron Emission Tomography for Detection of Cardiac Amyloidosis.

JACC Cardiovasc Imaging 2020 06 13;13(6):1337-1347. Epub 2020 May 13.

Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark; Department of Surgical Sciences, Radiology, Uppsala University, Uppsala, Sweden.

Objectives: This dual-site study evaluated the diagnostic accuracy of the method.

Background: Pittsburgh compound ([C]PIB) positron emission tomography (PIB-PET) has shown promise as a specific and noninvasive method for the diagnosis of cardiac amyloidosis (CA).

Methods: The study had 2 parts. In the initial study, 51 subjects were included, 36 patients with known CA and increased wall thickness (15 immunoglobulin light chain [AL] and 21 transthyretin [ATTR] amyloidosis) and 15 control patients (7 were nonamyloid hypertrophic and 8 healthy volunteers). Subjects underwent PIB-PET and echocardiography. Sensitivity and specificity of PIB-PET were established for 2 simple semiquantitative approaches, standardized uptake value ratio (SUVR) and retention index (RI). The second part of the study included 11 amyloidosis patients (5 AL and 6 hereditary ATTR) without increased wall thickness to which the optimal cutoff values of SUVR (>1.09) and RI (>0.037 min) were applied prospectively.

Results: The diagnostic accuracy of visual inspection of [C]PIB uptake was 100% in discriminating CA patients with increased wall thickness from controls. Semiquantitative [C]PIB uptake discriminated CA from controls with a 94% (95% confidence interval [CI]: 80% to 99%) sensitivity for both SUVR and RI and specificity of 93% (95% CI: 66% to 100%) for SUVR and 100% (95% CI: 75% to 100%) for RI. [C]PIB uptake was significantly higher in AL-CA than in ATTR-CA patients (p < 0.001) and discriminated AL-CA from controls with 100% (95% CI: 88% to 100%) accuracy for both the semiquantitative measures. In the prospective group without increased wall thickness, RI was elevated compared to controls (p = 0.001) and 5 of 11 subjects were evaluated as [C]PIB PET positive.

Conclusions: In a dual-center setting, [C]PIB PET was highly accurate in detecting cardiac involvement in the main amyloid subtypes, with 100% accuracy in AL amyloidosis. A proportion of amyloidosis patients without known cardiac involvement were [C]PIB PET positive, indicating that the method may detect early stages of CA.
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http://dx.doi.org/10.1016/j.jcmg.2020.02.023DOI Listing
June 2020

Outcome and characteristics of non-measurable myeloma: A cohort study with population-based data from the Swedish Myeloma Registry.

Eur J Haematol 2020 May 22;104(5):376-382. Epub 2020 Feb 22.

Department of Medicine, Karolinska Institutet, Stockholm, Sweden.

Objective: We describe survival in patients with oligo- and non-secretory multiple myeloma (MM). We refer to the whole group as non-measurable MM and compare it with secretory MM.

Methods: Oligo-secretory MM was defined as M protein in serum <10 g/L and M protein in urine <200 measured as mg/day, mg/liter or mg/mmol creatinine. If patients had no M protein, they were defined as non-secretory. The groups were also subdivided by Free Light Chains (SFLC) level and ratio.

Results: Out of 4325 patients with symptomatic MM in the Swedish Myeloma Registry during 2008-2016 eligible for the study, 389 patients (9%) had non-measurable MM. Out of these, 253 patients (6%) had oligo-secretory and 136 (3%) had non-secretory MM. Median survival for secretory MM was 42.7 months, non-measurable MM 40.2 months, oligo-secretory MM 38.6 months, and non-secretory MM 44.6 months. Difference in overall observed survival was non-significant for all groups when compared with secretory MM. Within non-secretory MM, stem cell transplantation (SCT), 95% being auto-SCT, was significant for superior survival in multivariate analysis (HR 0.048. P = .0015).

Conclusion: In this population-based study, we found no difference in survival between oligo- or non-secretory MM when compared with secretory MM. SCT appears to be important also for patients with non-secretory disease.
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http://dx.doi.org/10.1111/ejh.13351DOI Listing
May 2020

Intrathecal immunoglobulins and neurofilament light after autologous haematopoietic stem cell transplantation for multiple sclerosis.

Mult Scler 2020 10 26;26(11):1351-1359. Epub 2019 Jul 26.

Department of Neuroscience, Uppsala University, Uppsala, Sweden.

Background: Oligoclonal bands (OCB) are widely believed to be stable over time and rarely affected by disease-modifying treatment in MS. It is presently unknown how intrathecal immunoglobulin production and other cerebrospinal fluid (CSF) biomarkers are impacted by a highly efficacious procedure such as autologous haematopoietic stem cell transplantation (aHSCT).

Objective: To describe the evolution of intrathecal immunoglobulin and neurofilament light (NFL) over time in MS patients treated with aHSCT.

Methods: In this retrospective study, available data from previously made CSF investigations in 46 patients treated with aHSCT were analysed.

Results: After a median follow-up time of 745 days, immunoglobulin G (IgG) OCB remained detectable in 74% of patients, the proportion of patients with a pathological IgG index went down from 70% to 46%, and the proportion of patients with a pathological NFL went down from 72% to 24%. In patients with follow-up time >1500 days, IgG OCB were detectable in 50% of patients, 14% had a pathological IgG index and none a pathological NFL.

Conclusions: Intrathecal immunoglobulin production and NFL were lower after treatment with aHSCT, decreased over time and were normalised in a significant portion of patients. This challenges the notion that OCB are unaffected by therapeutic intervention in MS.
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http://dx.doi.org/10.1177/1352458519863983DOI Listing
October 2020

Sustained remission in multiple sclerosis after hematopoietic stem cell transplantation.

Acta Neurol Scand 2019 Nov 5;140(5):320-327. Epub 2019 Aug 5.

Department of Neuroscience, Uppsala University, Uppsala, Sweden.

Objectives: To determine whether treatment with autologous hematopoietic stem cell transplantation (HSCT) can induce sustained complete remission in patients with multiple sclerosis (MS).

Material And Methods: Case series of patients with relapsing-remitting MS (n = 10) treated at a single center between 2004 and 2007 and followed up for 10 years. The patients were treated with a BEAM/ATG conditioning regimen (n = 9) or a cyclophosphamide/ATG conditioning regimen (n = 1) followed by infusion of unmanipulated autologous hematopoietic stem cells. The primary endpoint was sustained complete remission. Sustained complete remission was defined as "no evidence of disease activity-4," sustained for a period of at least 5 years without any ongoing disease-modifying treatment. Furthermore, MS was considered as "resolved" if intrathecal IgG production and cerebrospinal fluid neurofilament light levels were normalized as well.

Results: Five out of 10 patients were in sustained complete remission at the end of the study. In three of them, MS was resolved.

Conclusions: Our data demonstrate that sustained complete remission after autologous HSCT for MS is possible.
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http://dx.doi.org/10.1111/ane.13147DOI Listing
November 2019

High Graft-versus-Host Disease-Free, Relapse/Rejection-Free Survival and Similar Outcome of Related and Unrelated Allogeneic Stem Cell Transplantation for Aplastic Anemia: A Nationwide Swedish Cohort Study.

Biol Blood Marrow Transplant 2019 10 4;25(10):1970-1974. Epub 2019 Jun 4.

Section of Hematology and Coagulation, Sahlgrenska University Hospital, Gothenburg, Sweden; Institute of Medicine, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.

Allogeneic stem cell transplantation (SCT) as primary treatment for aplastic anemia (AA) is being increasingly used. Yet, age, stem cell source, and donor type are important outcome factors. We have recently performed a nationwide cohort study of all patients with AA in Sweden diagnosed from 2000 to 2011 and now present outcome data on SCT patients. In total, 68 patients underwent SCT, and 63% of them had failed immunosuppressive therapy. We found that, with a median follow-up of 109 months (range, 35 to 192 months), 5-year overall survival (OS) for all patients was 86.8%, whereas graft-versus-host disease-free, relapse/rejection-free survival (GRFS) at 5 years was 69.1%. There was no survival impact regarding the donor type or stem cell source. Patients aged ≥40 years had a higher transplant-related mortality (29.4% versus 7.8%; P = .023), which translated into a lower 5-year OS: 70.6% versus 92.2% (P = .022) and a trend of lower GRFS (52.9% versus 74.5%; P = .069). In conclusion, we found in this real-world setting that both OS and GRFS were high, but SCT for patients with AA aged ≥40 years is problematic, and clinical trials addressing this issue are warranted.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.032DOI Listing
October 2019

Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial.

JAMA 2019 01;321(2):165-174

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Importance: Hematopoietic stem cell transplantation (HSCT) represents a potentially useful approach to slow or prevent progressive disability in relapsing-remitting multiple sclerosis (MS).

Objective: To compare the effect of nonmyeloablative HSCT vs disease-modifying therapy (DMT) on disease progression.

Design, Setting, And Participants: Between September 20, 2005, and July 7, 2016, a total of 110 patients with relapsing-remitting MS, at least 2 relapses while receiving DMT in the prior year, and an Expanded Disability Status Scale (EDSS; score range, 0-10 [10 = worst neurologic disability]) score of 2.0 to 6.0 were randomized at 4 US, European, and South American centers. Final follow-up occurred in January 2018 and database lock in February 2018.

Interventions: Patients were randomized to receive HSCT along with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg) (n = 55) or DMT of higher efficacy or a different class than DMT taken during the previous year (n = 55).

Main Outcomes And Measures: The primary end point was disease progression, defined as an EDSS score increase after at least 1 year of 1.0 point or more (minimal clinically important difference, 0.5) on 2 evaluations 6 months apart, with differences in time to progression estimated as hazard ratios.

Results: Among 110 randomized patients (73 [66%] women; mean age, 36 [SD, 8.6] years), 103 remained in the trial, with 98 evaluated at 1 year and 23 evaluated yearly for 5 years (median follow-up, 2 years; mean, 2.8 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. Median time to progression could not be calculated in the HSCT group because of too few events; it was 24 months (interquartile range, 18-48 months) in the DMT group (hazard ratio, 0.07; 95% CI, 0.02-0.24; P < .001). During the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the HSCT group and increased (worsened) from 3.31 to 3.98 in the DMT group (between-group mean difference, -1.7; 95% CI, -2.03 to -1.29; P < .001). There were no deaths and no patients who received HSCT developed nonhematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events).

Conclusions And Relevance: In this preliminary study of patients with relapsing-remitting MS, nonmyeloablative HSCT, compared with DMT, resulted in prolonged time to disease progression. Further research is needed to replicate these findings and to assess long-term outcomes and safety.

Trial Registration: ClinicalTrials.gov Identifier: NCT00273364.
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http://dx.doi.org/10.1001/jama.2018.18743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439765PMC
January 2019

Family Mismatched Allogeneic Stem Cell Transplantation for Myelofibrosis: Report from the Chronic Malignancies Working Party of European Society for Blood and Marrow Transplantation.

Biol Blood Marrow Transplant 2019 03 5;25(3):522-528. Epub 2018 Nov 5.

Department of Stem Cell Transplantation, University Hospital Eppendorf, Hamburg, Germany.

This analysis included 56 myelofibrosis (MF) patients transplanted from family mismatched donor between 2009 and 2015 enrolled in the European Society for Blood and Marrow Transplantation database. The median age was 57years (range, 38 to 72); 75% had primary MF and 25% had secondary MF. JAK2 V617F was mutated in 61%. Donors were HLA mismatched at 2 or more loci. Stem cells were sourced from bone marrow in 66% and peripheral blood in 34%. The median CD34 cell dose was 4.8 × 10/kg (range, 1.7 to 22.9; n = 43). Conditioning was predominantly myeloablative in 70% and reduced intensity in the remainder. Regimens were heterogeneous with thiotepa, busulfan, fludarabine, and post-transplant cyclophosphamide used in 59%. The incidence of neutrophil engraftment by 28days was 82% (range, 70% to 93%), at a median of 21days (range, 19 to 23). At 2years the cumulative incidence of primary graft failure was 9% (95% CI 1% to 16%) and secondary graft failure was 13% (95% CI 4% to 22%). The cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV was 28% (95% CI 16% to 40%) and 9% (95% CI 2% to 17%) at 100days. The cumulative incidence of chronic GVHD at 1 year was 45% (95% CI 32% to 58%), but the cumulative incidence of death without chronic GVHD by 1 year was 20% (95% CI 10% to 31%). With a median follow-up of 32 months, the 1- and 2-year overall survival was 61% (95% CI 48% to 74%) and 56% (95% CI 41% to 70%), respectively. The 1- and 2- year progression-free survival was 58% (95% CI 45% to 71%) and 43% (95% CI 28% to 58%), respectively, with a 2-year cumulative incidence of relapse of 19% (95% CI 7% to 31%). The 2-year nonrelapse mortality was 38% (95% CI 24% to 51%). This retrospective study of MF allo-SCT using family mismatched donors demonstrated feasibility of the approach, timely neutrophil engraftment in over 80% of cases, and acceptable overall and progression-free survival rates with relapse rates not dissimilar to the unrelated donor setting. However, strategies to minimize the risk of graft failure and the relatively high nonrelapse mortality need to be used, ideally in a multicenter prospective fashion.
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http://dx.doi.org/10.1016/j.bbmt.2018.10.017DOI Listing
March 2019

Quantification of C-PIB kinetics in cardiac amyloidosis.

J Nucl Cardiol 2020 06 23;27(3):774-784. Epub 2018 Jul 23.

Department of Surgical Science, Uppsala University, Uppsala, Sweden.

Background: The purpose of this work was to determine the optimal tracer kinetic model of C-PIB and to validate the use of the simplified methods retention index (RI) and standardized uptake value (SUV) for quantification of cardiac C-PIB uptake in amyloidosis.

Methods And Results: Single-tissue, reversible and irreversible two-tissue models were fitted to data from seven cardiac amyloidosis patients who underwent C-PIB PET scans and arterial blood sampling for measurement of blood radioactivity and metabolites. The irreversible two-tissue model (2Tirr) best described cardiac C-PIB uptake. RI and SUV showed high correlation with the rate of irreversible binding (K) from the 2Tirr model (r=0.95 and r=0.94). Retrospective data from 10 amyloidosis patients and 5 healthy controls were analyzed using RI, SUV, as well as compartment modelling with a population-average metabolite correction. All measures were higher in amyloidosis patients than in healthy controls (p=.001), but with an overlap between groups for K.

Conclusion: An irreversible two-tissue model best describes the C-PIB uptake in cardiac amyloidosis. RI and SUV correlate well with K from the 2Tirr model. RI and SUV discriminate better between amyloidosis patients and controls than K based on population-average metabolite correction.
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http://dx.doi.org/10.1007/s12350-018-1349-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326793PMC
June 2020

Outcome of patients with Myelofibrosis relapsing after allogeneic stem cell transplant: a retrospective study by the Chronic Malignancies Working Party of EBMT.

Br J Haematol 2018 08 29;182(3):418-422. Epub 2018 May 29.

University Hospital Eppendorf, Hamburg, Germany.

Allogeneic Haematopoietic Stem Cell Transplant (allo-HSCT) remains the only curative approach for Myelofibrosis (MF). Scarce information exists in the literature on the outcome and, indeed, management of those MF patients who relapse following transplant. We hereby report on the management and outcome of 202 patients who relapsed post allo-HSCT for MF.
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http://dx.doi.org/10.1111/bjh.15407DOI Listing
August 2018

Low response rate to ATG-based immunosuppressive therapy in very severe aplastic anaemia - A Swedish nationwide cohort study.

Eur J Haematol 2018 Jun 10;100(6):613-620. Epub 2018 Apr 10.

Institute of Medicine, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.

Objectives: Antithymocyte globulin (ATG)-based immunosuppression remains a cornerstone in aplastic anaemia (AA) treatment. However, most ATG studies are not population-based and knowledge about real-world results concerning response and outcome could offer important information for treating physicians.

Methods: We have recently performed a nationwide retrospective cohort study on all AA patients diagnosed in Sweden in 2000-2011 and now present treatment and outcome data on patients receiving first-line ATG. In total, 158 patients showed a 47.0% response rate which was similar in all age groups (range 41.5%-51.7%) with no difference regarding ATG formulation. The response was significantly associated with severity grade-especially at time of treatment initiation: very severe (VSAA) 22.7%; severe (SAA) 54.5% (P < .001); and non-severe 88.5% (P < .001). A logistic regression-based predictive model indicated that VSAA patients with an absolute reticulocyte count <25 × 10 /L had only a 19% probability of response. In a multivariable analysis, age and VSAA at the time of treatment were the independent factors for inferior survival.

Conclusions: Real-world VSAA patients respond poorly to ATG which indicates the need for a different treatment approach. Our findings suggest that age alone should not be a discriminating factor for administering ATG treatment.
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http://dx.doi.org/10.1111/ejh.13057DOI Listing
June 2018

Outcome and survival of myeloma patients diagnosed 2008-2015. Real-world data on 4904 patients from the Swedish Myeloma Registry.

Haematologica 2018 03 7;103(3):506-513. Epub 2017 Dec 7.

Department of Medicine and Division of Hematology, University of Iceland, Reykjavik, Iceland.

Epidemiology and outcome of myeloma are mainly reported from large university centers and collaborative groups, and do not represent 'real-world' patients. The Swedish Myeloma Registry is a prospective population-based registry documenting characteristics, treatment and outcome in newly diagnosed myeloma, including asymptomatic and localized forms, with the purpose of improving disease management and outcome. This report presents information on patients diagnosed between 2008 and 2015, including data on first-line treatment in patients diagnosed up to 2014, with a follow up until December 2016. We present age-adjusted incidence, patients' characteristics at baseline, treatment, response, and survival. Baseline data were available with a 97% coverage in 4904 patients (median age 71 years, males 70 years, females 73 years; 72% were 65 years or older), and at 1-year follow up in 3558 patients with symptomatic disease (92% of patients initially reported). The age-adjusted incidence was 6.8 myeloma cases per 100,000 inhabitants per year. Among initially symptomatic patients (n=3988), 77% had osteolytic lesions or compression fractures, 49% had anemia, 18% impaired kidney function, and 13% hypercalcemia. High-dose therapy with autologous stem cell transplantation was given to 77% of patients aged up to 66 years, and to 22% of patients aged 66-70 years. In the study period, 68% received bortezomib, thalidomide, and/or lenalidomide as part of the first-line treatment, rising from 31% in 2008 to 81% in 2014. In active myeloma, the median relative survival of patients aged 65 years or under was 7.7 years, and 3.4 years in patients aged 66 years and over. Patients diagnosed with myeloma in more recent years were associated with significantly higher rates of complete or very good partial remission (<0.05), and with a significantly higher survival, with a Hazard Ratio (HR) of 0.84 (95%CI: 0.77-0.92; <0.05). There was a small, but significant survival benefit in patients treated at university hospitals (HR 0.93; 95%CI: 0.87-0.99; <0.05). We report here on a near complete 'real-world' population of myeloma patients during an 8-year period; a period in which newer drugs were implemented into standard practice. The overall incidence and median age were both higher than in most previous studies, indicating a more complete coverage of older patients. Myeloma survival in Sweden is comparable to other large registry studies, and responses and survival improved during the study period.
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http://dx.doi.org/10.3324/haematol.2017.178103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830385PMC
March 2018

Incidence and outcome of acquired aplastic anemia: real-world data from patients diagnosed in Sweden from 2000-2011.

Haematologica 2017 10 27;102(10):1683-1690. Epub 2017 Jul 27.

South Älvsborg Hospital Borås, Sweden.

A plastic anemia is a rare life-threatening disease. However, since the introduction of immunosuppressive therapy and allogeneic stem cell transplantation, the outcome has improved considerably, and the 5-year survival is reported to be 70-80% in selected patient cohorts. Yet, contemporary population-based data on incidence and survival are lacking. We performed a national retrospective study to determine the incidence, treatment, and survival of patients with aplastic anemia diagnosed in Sweden from 2000-2011. Patients were included via the National Patient Registry, and diagnosed according to the Camitta criteria. In total, 257 confirmed cases were identified, with an overall incidence of 2.35 (95% CI: 2.06-2.64) cases per million inhabitants per year. Median age was 60 years (range: 2-92), and median follow up was 76 (0-193) months. Primary treatments included immunosuppressive therapy (63%), allogenic stem cell transplantation (10%), or single-agent cyclosporine/no specific therapy (27%). The 5-year survival was 90.7% in patients aged 0-18 years, 90.5% in patients aged 19-39 years, 70.7% in patients aged 40-59 years, and 38.1% in patients aged ≥60 years. Multivariate analysis showed that age (both 40-59 and ≥60 age groups), very severe aplastic anemia and single-agent cyclosporine/no specific therapy were independent risk factors for inferior survival. In conclusion, younger aplastic anemia patients experience a very good long-term survival, while that of patients ≥60 years in particular remains poor. Apparently, the challenge today is to improve the management of older aplastic anemia patients, and prospective studies to address this medical need are warranted.
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http://dx.doi.org/10.3324/haematol.2017.169862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622852PMC
October 2017

Incidence, characteristics, and outcome of solitary plasmacytoma and plasma cell leukemia. Population-based data from the Swedish Myeloma Register.

Eur J Haematol 2017 Sep 28;99(3):216-222. Epub 2017 Jun 28.

Hematology, Skane University Hospital, Malmö, Sweden.

Solitary plasmacytoma (SP) and plasma cell leukemia (PCL) are uncommon (3-6%) types of plasma cell disease. The risk of progression to symptomatic multiple myeloma (MM) is probably important for the outcome of SP. PCL is rare and has a dismal outcome. In this study, we report on incidence and survival in PCL/SP, and progression to MM in SP, using the prospective observational Swedish Multiple Myeloma Register designed to document all newly diagnosed plasma cell diseases in Sweden since 2008. Both solitary bone plasmacytoma (SBP) (n=124) and extramedullary plasmacytoma (EMP) (n=67) have better overall survival (OS) than MM (n=3549). Progression to MM was higher in SBP than in EMP (35% and 7% at 2 years, respectively), but this did not translate into better survival in EMP. In spite of treatment developments, the OS of primary PCL is still dismal (median of 11 months, 0% at 5 years). Hence, there is a great need for diagnostic and treatment guidelines as well as prospective studies addressing the role for alternative treatment options, such as allogeneic stem cell transplantation and monoclonal antibodies in the treatment of PCL.
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http://dx.doi.org/10.1111/ejh.12907DOI Listing
September 2017

Successful autologous haematopoietic stem cell transplantation for refractory myasthenia gravis - a case report.

Neuromuscul Disord 2017 Jan 28;27(1):90-93. Epub 2016 Sep 28.

Department of Medical Sciences, Division of Haematology, University Hospital, Uppsala, Sweden.

Myasthenia gravis (MG) is an autoimmune disease, with immune reactivity against the post-synaptic endplate of the neuromuscular junction. Apart from symptomatic treatment with choline esterase blockers, many patients also require immunomodulatory treatment. Despite existing treatment options, some patients are treatment refractory. We describe a patient with severe MG refractory to corticosteroids, four oral immunosuppressants, cyclophosphamide, rituximab and bortezomib who was treated with autologous haematopoietic stem cell transplantation. Two years after this, the patient has significantly improved in objective tests and in quality of life and leads an active life. Diplopia is her only remaining symptom and she is completely free of medication for MG. We believe that autologous haematopoietic stem cell transplantation can be an effective therapeutic option for carefully selected cases of severe, treatment refractory MG.
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http://dx.doi.org/10.1016/j.nmd.2016.09.020DOI Listing
January 2017

Optimizing production of Fc-amidated peptides by Chinese hamster ovary cells.

BMC Biotechnol 2015 Oct 16;15:95. Epub 2015 Oct 16.

Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030-3401, USA.

Background: Amidation of the carboxyl terminal of many peptides is essential for full biological potency, often increasing receptor binding and stability. The single enzyme responsible for this reaction is peptidylglycine α-amidating monooxygenase (PAM: EC 1.14.17.3), a copper- and ascorbate-dependent Type I membrane protein.

Methods: To make large amounts of high molecular weight amidated product, Chinese hamster ovary (CHO) cells were engineered to express exogenous PAM. To vary access of the enzyme to its substrate, exogenous PAM was targeted to the endoplasmic reticulum, trans-Golgi network, endosomes and lysosomes or to the lumen of the secretory pathway.

Results: PAM was equally active when targeted to each intracellular location and assayed in homogenates. Immunocytochemical analyses of CHO cells and a pituitary cell line demonstrated that targeting of exogenous PAM was partially successful. PAM substrates generated by expressing peptidylglycine substrates (glucagon-like peptide 1-Gly, peptide YY-Gly and neuromedin U-Gly) fused to the C-terminus of immunoglobulin Fc in CHO cell lines producing targeted PAM. The extent of amidation of the Fc-peptides was determined by mass spectrometry and amidation-specific enzyme immunoassays. Amidation was inhibited by copper chelation, but was not enhanced by the addition of additional copper or ascorbate.

Conclusions: Peptide amidation was increased over endogenous levels by exogenous PAM, and targeting PAM to the endoplasmic reticulum or trans-Golgi network increased peptide amidation compared to endogenous CHO PAM.
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http://dx.doi.org/10.1186/s12896-015-0210-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609047PMC
October 2015

Second allogeneic stem cell transplant for aplastic anaemia: a retrospective study by the Severe Aplastic Anaemia Working Party of the European Society for Blood and Marrow Transplantation.

Br J Haematol 2015 Nov 25;171(4):606-14. Epub 2015 Aug 25.

Paediatric Haematology, Institute G. Gaslini, Genova, Italy.

We analysed the outcome of a second allogeneic haematopoietic stem cell transplant (alloHSCT) in 162 patients reported to the European Society for Blood and Marrow Transplantation between 1998 and 2009. Donor origin was a sibling in 110 and an unrelated donor in 52 transplants, respectively. The stem cell source was bone marrow in 31% and peripheral blood in 69% of transplants. The same donor as for the first alloHSCT was used in 81% of transplants whereas a change in the choice of stem cell source was reported in 56% of patients, mainly from bone marrow to peripheral blood. Neutrophil and platelet engraftment occurred in 85% and 72% of patients, after a median time of 15 and 17 days, respectively. Grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD occurred in 21% and 37% of patients, respectively. Graft failure (GF) occurred in 42 patients (26%). After a median follow-up of 3·5 years, the 5-year overall survival (OS) was 60·7%. In multivariate analysis, the only factor significantly associated with a better outcome was a Karnofsky/Lansky score ≥80 (higher OS). We conclude that a second alloHSCT is feasible rescue option for GF in SAA, with a successful outcome in 60% of cases.
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http://dx.doi.org/10.1111/bjh.13650DOI Listing
November 2015

Secretion of Fc-amidated peptide fusion proteins by Chinese hamster ovary cells.

BMC Biotechnol 2015 Jun 27;15:61. Epub 2015 Jun 27.

Department of Neuroscience, UCONN Health Center, 263 Farmington Avenue, Farmington, CT, 06030-3401, USA.

Background: The therapeutic use of α-amidated peptides (e.g. calcitonin, glucagon-like peptide) has increased dramatically, but there are major impediments to wider use of such peptides. Larger peptides are expensive to synthesize, and short plasma half-lives frequently limit the clinical circumstances in which the peptides would be useful. Both problems are potentially solved by producing peptides as fusions with the Fc region of human immunoglobulin.

Methods: Glucagon-like peptide 1 (GLP1), peptide YY (PYY) and neuromedin U (NMU) were expressed and purified from stable CHO lines; since the α-amide group is essential for full biological potency of many peptides, Fc-fusion peptides were expressed in CHO lines stably expressing the α-amidating enzyme, peptidylglycine α-amidating monooxygenase (PAM: EC 1.14.17.3). Purified fusion proteins were analyzed intact and after HRV3C rhinovirus protease cleavage, at a site in the linker separating the Fc region from the peptide, by mass spectrometry and amide-specific immunoassays.

Results: The Fc fusions were expressed at 1-2.5 μg/mg cell protein and secreted at 5-20% of cell content per hour, in a peptide-specific manner. CHO cells express measurable endogenous PAM activity, amidating 25% of Fc-PYY and almost 90% of Fc-GLP1. Expression of exogenous PAM increased the level of peptide amidation to 50% of Fc-PYY and 95 % of Fc-NMU. The Fc-GLP1 fusions were 10,000-fold less active than synthetic GLP1 in a cell-receptor cyclic AMP-based assay, as expected since the amino terminal of GLP1 is essential for full biological activity. The Fc-PYY fusions were 100-fold less active than PYY-NH2 but 10-fold more active than non-amidated PYY-Gly.

Conclusions: This type of approach can be used for the production of stabilized α-amidated peptides aimed at clinical trials.
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http://dx.doi.org/10.1186/s12896-015-0173-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482046PMC
June 2015

Autologous hematopoietic stem cell transplantation in neuromyelitis optica: a registry study of the EBMT Autoimmune Diseases Working Party.

Mult Scler 2015 Feb 30;21(2):189-97. Epub 2014 Jul 30.

ADWP-EBMT Chair, Internal Medicine and Vascular Pathology Unit, Saint Louis Hospital, Assistance Publique des Hôpitaux de Paris, Paris 7 University, INSERM 976, France.

Background: Neuromyelitis optica (NMO) is an inflammatory autoimmune disorder of the central nervous system, hallmarked by pathogenic anti-aquaporin 4 antibodies. NMO prognosis is worse compared with multiple sclerosis.

Objective: The European Group for Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP) conducted a retrospective survey to analyze disease outcome following autologous stem cell transplantation (ASCT).

Methods: This retrospective multicenter study assessed the efficacy and safety of ASCT in 16 patients suffering from refractory NMO reported to the EBMT registry between 2001 and 2011.

Results: Fifteen patients were successfully mobilized with cyclophosphamide (Cy) and G-CSF, one with G-CSF alone. All patients received an unmanipulated autologous peripheral blood stem cell graft, after conditioning with BEAM plus anti-thymocyte globulin (ATG, n = 9 patients), thiotepa-Cy (n = 3) or Cy (200 mg/kg) plus ATG (n = 4). After a median follow-up of 47 months, three of 16 cases were progression and treatment free, while in the remaining 13 patients further treatments were administered for disability progression or relapse after ASCT. Altogether, relapse-free survival at three and five years was 31% and 10%, respectively, while progression-free survival remained 48% at three and five years.

Conclusions: In these NMO patients, highly resistant to conventional treatment, ASCT allows for temporary control of the disease, despite a tendency to progress or relapse in the long term.
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http://dx.doi.org/10.1177/1352458514541978DOI Listing
February 2015

Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience.

J Neurol Neurosurg Psychiatry 2014 Oct 19;85(10):1116-21. Epub 2014 Feb 19.

Department of Neuroscience, Uppsala University, Uppsala, Sweden Department of Neurology, Uppsala University Hospital, Uppsala, Sweden.

Background: Autologous haematopoietic stem cell transplantation (HSCT) is a viable option for treatment of aggressive multiple sclerosis (MS). No randomised controlled trial has been performed, and thus, experiences from systematic and sustained follow-up of treated patients constitute important information about safety and efficacy. In this observational study, we describe the characteristics and outcome of the Swedish patients treated with HSCT for MS.

Methods: Neurologists from the major hospitals in Sweden filled out a follow-up form with prospectively collected data. Fifty-two patients were identified in total; 48 were included in the study and evaluated for safety and side effects; 41 patients had at least 1 year of follow-up and were further analysed for clinical and radiological outcome. In this cohort, 34 patients (83%) had relapsing-remitting MS, and mean follow-up time was 47 months.

Results: At 5 years, relapse-free survival was 87%; MRI event-free survival 85%; expanded disability status scale (EDSS) score progression-free survival 77%; and disease-free survival (no relapses, no new MRI lesions and no EDSS progression) 68%. Presence of gadolinium-enhancing lesions prior to HSCT was associated with a favourable outcome (disease-free survival 79% vs 46%, p=0.028). There was no mortality. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%).

Conclusions: HSCT is a very effective treatment of inflammatory active MS and can be performed with a high degree of safety at experienced centres.
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http://dx.doi.org/10.1136/jnnp-2013-307207DOI Listing
October 2014

Structural and functional analysis of the GerD spore germination protein of Bacillus species.

J Mol Biol 2014 May 12;426(9):1995-2008. Epub 2014 Feb 12.

Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT 06030-3305, USA. Electronic address:

Spore germination in Bacillus species represents an excellent model system with which to study the molecular mechanisms underlying the nutritional control of growth and development. Binding of specific chemical nutrients to their cognate receptors located in the spore inner membrane triggers the germination process that leads to a resumption of metabolism in spore outgrowth. Recent studies suggest that the inner membrane GerD lipoprotein plays a critical role in the receptor-mediated activation of downstream germination events. The 121-residue core polypeptide of GerD (GerD⁶⁰⁻¹⁸⁰) from Geobacillus stearothermophilus forms a stable α-helical trimer in aqueous solution. The 2.3-Å-resolution crystal structure of the trimer reveals a neatly twisted superhelical rope, with unusual supercoiling induced by parallel triple-helix interactions. The overall geometry comprises three interleaved hydrophobic screws of interacting helices linked by short turns that have not been seen before. Using complementation analysis in a series of Bacillus subtilis gerD mutants, we demonstrated that alterations in the GerD trimer structure have profound effects on nutrient germination. This important structure-function relationship of trimeric GerD is supported by our identification of a dominant negative gerD mutation in B. subtilis. These results and those of others lead us to propose that GerD mediates clustering of germination proteins in the inner membrane of dormant spores and thus promotes the rapid and cooperative germination response to nutrients.
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http://dx.doi.org/10.1016/j.jmb.2014.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038265PMC
May 2014

Improved survival in myeloma patients: starting to close in on the gap between elderly patients and a matched normal population.

Br J Haematol 2014 Mar 9;164(5):684-93. Epub 2013 Dec 9.

Department of Medicine, Karolinska Institutet, Stockholm, Sweden.

The outcome for multiple myeloma patients has improved since the introduction of bortezomib, thalidomide and lenalidomide. However, studies comparing new and conventional treatment include selected patient groups. We investigated consecutive patients (n = 1638) diagnosed in a defined period and compared survival with a gender- and age-matched cohort Swedish population (n = 9 340 682). Median overall survival for non-high-dose treated patients was 2·8 years. The use of bortezomib, thalidomide or lenalidomide in first line therapy predicted a significantly longer overall survival (median 4·9 years) compared to conventional treatment (2·3 years). Among non-high-dose treated patients receiving at least 2 lines with bortezomib, thalidomide or lenalidomide, 69% and 63% have survived at 3 and 5 years as compared to 48% and 22% with conventional drugs and 88% and 79% in the matched cohort populations, respectively. The median overall survival in high-dose treated patients was 6·9 years. Of these patients, 84% survived at 3 years and 70% at 5 years as compared to 98% and 95% in the matched cohort population. Overall survival in the best non-high-dose treated outcome group is closing the gap with the matched cohort. Upfront use of new drugs is clearly better than waiting until later lines of treatment.
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http://dx.doi.org/10.1111/bjh.12685DOI Listing
March 2014

Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial.

Blood 2013 Jun 24;121(23):4647-54. Epub 2013 Apr 24.

Department of Medicine, Section of Hematology and Coagulation, Sahlgrenska University Hospital, Gothenburg, Sweden.

The Nordic Myeloma Study Group conducted an open randomized trial to compare bortezomib as consolidation therapy given after high-dose therapy and autologous stem cell transplantation (ASCT) with no consolidation in bortezomib-naive patients with newly diagnosed multiple myeloma. Overall, 370 patients were centrally randomly assigned 3 months after ASCT to receive 20 doses of bortezomib given during 21 weeks or no consolidation. The hypothesis was that consolidation therapy would prolong progression-free survival (PFS). The PFS after randomization was 27 months for the bortezomib group compared with 20 months for the control group (P = .05). Fifty-one of 90 patients in the treatment group compared with 32 of 90 controls improved their response after randomization (P = .007). No difference in overall survival was seen. Fatigue was reported more commonly by the bortezomib-treated patients in self-reported quality-of-life (QOL) questionnaires, whereas no other major differences in QOL were recorded between the groups. Consolidation therapy seemed to be beneficial for patients not achieving at least a very good partial response (VGPR) but not for patients in the ≥ VGPR category at randomization. Consolidation with bortezomib after ASCT in bortezomib-naive patients improves PFS without interfering with QOL. This trial was registered at www.clinicaltrials.gov as #NCT00417911.
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http://dx.doi.org/10.1182/blood-2012-11-464503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674665PMC
June 2013

A combination regimen of bortezomib, cyclophosphamide and betamethasone gives quicker, better and more durable response than VAD/CyBet regimens: results from a Swedish retrospective analysis.

Acta Haematol 2013 25;130(1):7-15. Epub 2013 Jan 25.

Division of Haematology, Department of Medicine, Karolinska Institutet Huddinge, Stockholm, Sweden.

Background: Induction therapy for multiple myeloma (MM) and remission status before high-dose treatment (HDT) have been shown to be prognostic factors for survival outcome, although the optimal induction therapy is yet to be defined.

Methods: We conducted a retrospective analysis of the impact of induction therapy on survival outcome before and after HDT in MM patients. The study included 236 consecutive patients who underwent HDT.

Results: One hundred and forty-two patients (62%) were treated with vincristine, doxorubicin and dexamethasone (VAD) or cyclophosphamide and betamethasone (CyBet) and 94 (38%) were treated with bortezomib, cyclophosphamide and betamethasone (VCB) as induction. Time to first and time to best response was faster in the VCB group than in the VAD/CyBet group, with 42 versus 75 (p < 0.001) and 54 versus 88 days (p < 0.001), respectively. After induction therapy, 49% of the patients in the VCB group and 38% in the VAD/CyBet group achieved a very good partial response or better. Multivariate analysis revealed younger age, lower International Staging System stage and induction treatment with VCB as variables associated with favourable time to progression.

Conclusions: Outcome measured as response and time to progression before and after HDT in MM differs depending on type of induction treatment and suggests that VCB is a highly effective induction regimen that confers a post-HDT advantage.
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http://dx.doi.org/10.1159/000345422DOI Listing
September 2013

Autologous stem cell transplantation for enteropathy-associated T-cell lymphoma: a retrospective study by the EBMT.

Blood 2013 Mar 29;121(13):2529-32. Epub 2013 Jan 29.

University of Eastern Finland/Clinical Medicine and Department of Medicine, Kuopio University Hospital, Kuopio, Finland.

Enteropathy-associated T-cell lymphoma (EATL) is a rare subtype of peripheral T-cell lymphomas with a poor prognosis. Autologous stem cell transplantation (ASCT) was retrospectively evaluated as a consolidation or salvage strategy for EATL. The analysis included 44 patients who received ASCT for EATL between 2000 and 2010. Thirty-one patients (70%) were in first complete or partial remission at the time of the ASCT. With a median follow-up of 46 months, relapse incidence, progression-free survival, and overall survival were 39%, 54%, and 59% at 4 years, respectively, with only one relapse occurring beyond 18 months posttransplant. There was a trend for better survival in patients transplanted in first complete or partial remission at 4 years (66% vs 36%; P = .062). ASCT is feasible in selected patients with EATL and can yield durable disease control in a significant proportion of the patients.
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http://dx.doi.org/10.1182/blood-2012-11-466839DOI Listing
March 2013

Evaluation of patients with cardiac amyloidosis using echocardiography, ECG and right heart catheterization.

Amyloid 2013 Mar 22;20(1):27-33. Epub 2013 Jan 22.

Department of Medical Sciences: Clinical Physiology, Uppsala University, Uppsala, Sweden.

Aims: To characterize patients with cardiac amyloidosis using echocardiography, electrocardiogram (ECG) and right heart catheterization (RHC).

Methods And Results: Fourteen patients with biopsy verified light chain or transthyretin cardiac amyloidosis were included. All patients had heart failure with markedly elevated NT-proBNP. Echocardiography demonstrated biventricular hypertrophy, left atrial enlargement and normal to slightly reduced left ventricular ejection fraction. Tissue Doppler septal é was low and median E/é was high. Within 6 months RHC was performed in eight of the patients. The restrictive filling pattern demonstrated by echocardiography corresponded well to median pulmonary wedge pressure (21 mmHg). Systolic pulmonary artery pressure (SPAP) was increased, whereas cardiac output and stroke volume were seen to be decreased with both methods. ECG demonstrated: low voltage (36%), abnormal R-progression (65%), ST-T abnormalities (71%) and high incidence of fibrillation (36%). In addition, a case report following the treatment of melphalan and dexamethasone is presented with improvement of hypertrophy, SPAP, left ventricular mass and é.

Conclusion: These findings should lead to a suspicion of cardiac amyloidosis and suggest further investigation.
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http://dx.doi.org/10.3109/13506129.2012.761967DOI Listing
March 2013

New autoimmune diseases after cord blood transplantation: a retrospective study of EUROCORD and the Autoimmune Disease Working Party of the European Group for Blood and Marrow Transplantation.

Blood 2013 Feb 17;121(6):1059-64. Epub 2012 Dec 17.

Eurocord, Hôpital Saint Louis Assistance Publique des Hôpitaux de Paris (AP-HP), University Paris VII, Paris, France.

To describe the incidence, risk factors, and treatment of autoimmune diseases (ADs) occurring after cord blood transplantation (CBT), we analyzed both CBT recipients reported to EUROCORD who had developed at least 1 new AD and those who had not. Fifty-two of 726 reported patients developed at least 1 AD within 212 days (range, 27-4267) after CBT. Cumulative incidence of ADs after CBT was 5.0% +/- 1% at 1 year and 6.6% +/- 1% at 5 years. Patients developing ADs were younger and had more nonmalignant diseases (P < .001). ADs target hematopoietic (autoimmune hemolytic anemia, n = 20; Evans syndrome, n = 9; autoimmune thrombocytopenia, n = 11; and immune neutropenia, n = 1) and other tissues (thyroiditis, n = 3; psoriasis, n = 2; Graves disease, n 1; membranous glomerulonephritis, n = 2; rheumatoid arthritis, n = 1; ulcerative colitis, n = 1; and systemic lupus erythematosus, n = 1). Four patients developed 2 ADs (3 cases of immune thrombocytopenia followed by autoimmune hemolytic anemia and 1 Evans syndrome with rheumatoid arthritis). By multivariate analysis, the main risk factor for developing an AD was nonmalignant disease as an indication for CBT (P = .0001). Hematologic ADs were most often treated with steroids, rituximab, and cyclosporine. With a median follow-up of 26 months (range, 2-91), 6 of 52 patients died as a consequence of ADs. We conclude that CBT may be followed by potentially life-threatening, mainly hematologic ADs.
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http://dx.doi.org/10.1182/blood-2012-07-445965DOI Listing
February 2013

In vivo visualization of amyloid deposits in the heart with 11C-PIB and PET.

J Nucl Med 2013 Feb 13;54(2):213-20. Epub 2012 Dec 13.

Platform for Preclinical PET, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.

Unlabelled: Cardiac amyloidosis is a differential diagnosis in heart failure and is associated with high mortality. There is currently no noninvasive imaging test available for specific diagnosis. N-[methyl-(11)C]2-(4'-methylamino-phenyl)-6-hydroxybenzothiazole ((11)C-PIB) PET is used in the evaluation of brain amyloidosis. We evaluated the potential use of (11)C-PIB PET in systemic amyloidosis affecting the heart.

Methods: Patients (n = 10) diagnosed with systemic amyloidosis-including heart involvement of either monoclonal immunoglobulin light-chain (AL) or transthyretin (ATTR) type-and healthy volunteers (n = 5) were investigated with PET/CT using (11)C-PIB to study cardiac amyloid deposits and with (11)C-acetate to measure myocardial blood flow to study the impact of global and regional perfusion on PIB retention.

Results: Myocardial (11)C-PIB uptake was visually evident in all patients 15-25 min after injection and was not seen in any volunteer. A significant difference in (11)C-PIB retention in the heart between patients and healthy controls was found. The data indicate that myocardial amyloid deposits in patients diagnosed with systemic amyloidosis could be visualized with (11)C-PIB. No correlation between (11)C-PIB retention index and myocardial blood flow as measured with (11)C-acetate was found on the global level, whereas a positive correlation on the segmental level was seen in a single patient.

Conclusion: (11)C-PIB and PET could be a method to study systemic amyloidosis of type AL and ATTR affecting the heart and should be investigated further both as a diagnostic tool and as a noninvasive method for treatment follow-up.
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http://dx.doi.org/10.2967/jnumed.111.102053DOI Listing
February 2013

Plerixafor and granulocyte colony-stimulating factor for first-line steady-state autologous peripheral blood stem cell mobilization in lymphoma and multiple myeloma: results of the prospective PREDICT trial.

Haematologica 2013 Feb 14;98(2):172-8. Epub 2012 Sep 14.

Nottingham University Hospital (City Campus), Nottingham, UK.

In Europe, the combination of plerixafor + granulocyte colony-stimulating factor is approved for the mobilization of hematopoietic stem cells for autologous transplantation in patients with lymphoma and myeloma whose cells mobilize poorly. The purpose of this study was to further assess the safety and efficacy of plerixafor + granulocyte colony-stimulating factor for front-line mobilization in European patients with lymphoma or myeloma. In this multicenter, open label, single-arm study, patients received granulocyte colony-stimulating factor (10 μg/kg/day) subcutaneously for 4 days; on the evening of day 4 they were given plerixafor (0.24 mg/kg) subcutaneously. Patients underwent apheresis on day 5 after a morning dose of granulocyte colony-stimulating factor. The primary study objective was to confirm the safety of mobilization with plerixafor. Secondary objectives included assessment of efficacy (apheresis yield, time to engraftment). The combination of plerixafor + granulocyte colony-stimulating factor was used to mobilize hematopoietic stem cells in 118 patients (90 with myeloma, 25 with non-Hodgkin's lymphoma, 3 with Hodgkin's disease). Treatment-emergent plerixafor-related adverse events were reported in 24 patients. Most adverse events occurred within 1 hour after injection, were grade 1 or 2 in severity and included gastrointestinal disorders or injection-site reactions. The minimum cell yield (≥ 2 × 10(6) CD34(+) cells/kg) was harvested in 98% of patients with myeloma and in 80% of those with non-Hodgkin's lymphoma in a median of one apheresis. The optimum cell dose (≥ 5 × 10(6) CD34(+) cells/kg for non-Hodgkin's lymphoma or ≥ 6 × 10(6) CD34(+) cells/kg for myeloma) was harvested in 89% of myeloma patients and 48% of non-Hodgkin's lymphoma patients. In this prospective, multicenter European study, mobilization with plerixafor + granulocyte colony-stimulating factor allowed the majority of patients with myeloma or non-Hodgkin's lymphoma to undergo transplantation with minimal toxicity, providing further data supporting the safety and efficacy of plerixafor + granulocyte colony-stimulating factor for front-line mobilization of hematopoietic stem cells in patients with non-Hodgkin's lymphoma or myeloma.
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http://dx.doi.org/10.3324/haematol.2012.071456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561422PMC
February 2013

Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study.

Eur J Haematol 2012 Jun 30;88(6):485-96. Epub 2012 Mar 30.

Department of Medicine, Lidköping Hospital, Lidköping, Sweden.

Objectives: Thalidomide and bortezomib have been frequently used for second-line therapy in patients with myeloma relapsing after or refractory to initial melphalan-based treatment, but no randomized trials have been published comparing these two treatment alternatives.

Methods: Thalidomide- and bortezomib-naïve patients with melphalan refractory myeloma were randomly assigned to low-dose thalidomide + dexamethasone (Thal-Dex) or bortezomib + dexamethasone (Bort-Dex). At progression on either therapy, the patients were offered crossover to the alternative drug combination. An estimated 300 patients would be needed for the trial to detect a 50% difference in median PFS between the treatment arms.

Results: After inclusion of 131 patients, the trial was prematurely closed because of low accrual. Sixty-seven patients were randomized to Thal-Dex and 64 to Bort-Dex. Progression-free survival was similar (median, 9.0 months for Thal-Dex and 7.2 for Bort-Dex). Response rate was similar (55% for Thal-Dex and 63% for Bort-Dex), but time to response was shorter (P < 0.05) and the VGPR rate higher (P < 0.01) for Bort-Dex. Time-to-other treatment after crossover was similar (median, 13.2 months for Thal-Dex and 11.2 months for Bort-Dex), as was overall survival (22.8 months for Thal-Dex and 19.0 for Bort-Dex). Venous thromboembolism was seen in seven patients and cerebrovascular events in four patients in the Thal-Dex group. Severe neuropathy, reactivation of herpes virus infections, and mental depression were more frequently observed in the Bort-Dex group. In the quality-of-life analysis, no difference was noted for physical function, pain, and global quality of life. Fatigue and sleep disturbances were significantly more prevalent in the Bort-Dex group.

Conclusions: Thalidomide (50-100 mg daily) in combination with dexamethasone seems to have an efficacy comparable with that of bortezomib and dexamethasone in melphalan refractory myeloma. However, the statistical strength of the results in this study is limited by the low number of included patients.
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http://dx.doi.org/10.1111/j.1600-0609.2012.01775.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492844PMC
June 2012