Publications by authors named "André Tichelli"

144 Publications

Systematic reviews in hematopoietic cell transplantation and cellular therapy: considerations and guidance from the American Society for Transplantation and Cellular Therapy, European Society for Blood and Marrow Transplantation, and the Center for International Blood and Marrow Transplant Research late effects and quality of life working committee.

Bone Marrow Transplant 2021 Apr 29;56(4):786-797. Epub 2021 Jan 29.

Center for International Blood and Marrow Transplant Research, Milwaukee, WI, USA.

Systematic reviews apply rigorous methodologies to address a pre-specified, clearly formulated clinical research question. The conclusion that results is often cited to more robustly inform decision-making by clinicians, third-party payers and managed care organizations about the clinical question of interest. While systematic reviews provide a rigorous standard, they may be unfeasible when the task is to create general disease-focused guidelines comprised of multiple clinical practice questions versus a single major clinical practice question. Collaborating transplantation and cellular therapy societal committees also recognize that the quantity and or quality of reference sources may be insufficient for a meaningful systematic review. As the conduct of systematic reviews has evolved over time in terms of grading systems, reporting requirements and use of technology, here we provide current guidance in methodologies, resources for reviewers, and approaches to overcome challenges in conducting systematic reviews in transplantation and cellular therapy.
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http://dx.doi.org/10.1038/s41409-020-01199-1DOI Listing
April 2021

Cellular immunotherapy with multiple infusions of in vitro-expanded haploidentical natural killer cells after autologous transplantation for patients with plasma cell myeloma.

Cytotherapy 2021 Apr 29;23(4):329-338. Epub 2020 Nov 29.

Clinical and Diagnostic Hematology, University Hospital Basel, Basel, Switzerland.

Background Aims: To investigate the feasibility and safety of haploidentical natural killer (NK) cell infusions as consolidation immunotherapy after autologous stem cell transplant (ASCT) in patients with plasma cell myeloma.

Methods: Ten patients (median age, 59 years) received induction treatment followed by high-dose melphalan (200 mg/m) at day -1, ASCT at day 0 and increasing NK cell doses (1.5 × 10, 1.5 × 10 and multiple doses of 1.0 × 10 cells/kg body weight) from day +1 to day +30 after ASCT. NK cells were harvested and purified from peripheral blood of haploidentical donors and expanded for 19 days with interleukin (IL)-2 and IL-15 under Good Manufacturing Practice conditions.

Results: NK cell numbers increased 56.0-fold (37.4- to 75.5-fold). Patients received a median of 3.8 × 10 (0.9-5.7 × 10) NK cells/kg body weight in six (three to eight) infusions. Multiparametric mass cytometry analysis demonstrated an altered surface receptor repertoire of expanded NK cells with increased degranulation and cytokine production activities but diminished expression of perforin. Donor NK cells were detectable in the peripheral blood, peaking 1 h after each dose (up to 90% donor NK cells). The treatment was safe and well tolerated, without evidence of graft-versus-host disease. Comparison with a control patient population receiving ASCT without NK cell infusions showed no significant difference in relapse, progression-free survival and overall survival.

Conclusions: This study demonstrates reliable manufacturing of high numbers of activated NK cells for multiple-dose infusions and safe administration of these cellular products. The trial was registered at ClinicalTrials.gov (identifier no. NCT01040026).
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http://dx.doi.org/10.1016/j.jcyt.2020.09.009DOI Listing
April 2021

New-onset Post-transplant Diabetes and Therapy in Long-term Survivors After Allogeneic Hematopoietic Stem Cell Transplantation.

In Vivo 2020 Nov-Dec;34(6):3545-3549

Department of Endocrinology, Diabetology and Metabolism, Bürgerspital Solothurn, Solothurn, Switzerland.

Background: Survival after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has increased but so have long-term sequelae. New-onset post-transplant diabetes mellitus (PTDM) occurs frequently following allo-HSCT.

Patients And Methods: Study endpoints were incidence and risk factors of PDTM. We studied 599 adult patients suffering from either acute myeloid leukemia n=220), acute lymphoblastic leukemia (n=79), chronic myeloid leukemia (n=22), myelodysplastic syndrome/myeloproliferative neoplasm (n=105), chronic lymphocytic leukemia (n=37), lymphoma/myeloma (n=116, or non-malignant disorders (e.g. bone marrow failure, hemoglobinopathies) (n=20) who underwent myeloablative (466; 77.8%) or non-myeloablative (131; 21.9%) allo-HSCT between 2006 and 2016.

Results: Altogether, 39 patients (6.5%) developed PTDM. In a competing-risk analysis, time to PTDM was associated with acute grade 2-4 graft-versus-host-disease (p=0.017). Further cardiovascular risk factors were hypertension (n=145; 24.2%), coronary artery disease (n=36, 6%), dyslipidemia (n=139; 23.3%), and stroke (n=12; 2%).

Conclusion: After allo-HSCT, a significant number of patients developed PTDM and patients with acute graft-versus-host-disease were found to have a higher risk for PTDM. Long-term and continuous follow-up for diabetes and cardiovascular risk factors after HSCT is important in order to be able to provide timely and appropriate treatment.
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http://dx.doi.org/10.21873/invivo.12197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811658PMC
August 2020

Very long-term follow-up of aplastic anemia treated with immunosuppressive therapy or allogeneic hematopoietic cell transplantation.

Ann Hematol 2020 Nov 19;99(11):2529-2538. Epub 2020 Sep 19.

Division of Hematology, University Hospital, Basel, Switzerland.

Introduction: Since the 1970s outcome of aplastic anemia (AA) patients has improved significantly due to the introduction of immunosuppressive therapy (IST) and allogeneic hematopoietic transplantation (HCT). However, patients may suffer from persistent disease, relapse, clonal evolution, graft-versus-host disease and other late effects. Here, we analyse very long-term outcome of all AA patients at our institution comparing not only survival, but also response status and complications.

Methods: Patient charts of all 302 AA patients treated between 1973 and 2017 at the University Hospital Basel, Switzerland, were retrospectively analysed.

Results: First line treatment was IST in 226 (75%) and HCT in 76 (25%) patients. Overall survival at 30 years was similar in patients treated initially by HCT and IST (44% (±14%), and 40% (± 9%) respectively, with better results in more recent years. Partial and no response occurred more frequently after IST, relapse incidence after IST was 24 %, whereas non-engraftment and graft failure was documented in 15 patients (19 %) after HCT. Clonal evolution to myelodysplastic syndrome / acute myeloid leukemia was 16 % at 25 years in IST patients, 1.3 % in HCT patients, iron overload (18 versus 4 %, p = 0.002) and cardiovascular events (11 versus 1 %, p=0.011) occured significantly more often in IST than HCT treated patients. The majority of long-term survivors, 96% of those alive at 25 years, were in complete remission at last follow up, irrespective of the initial treatment modality.

Conclusion: Very long term survivors after AA are those with stable hematopoietic recovery.
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http://dx.doi.org/10.1007/s00277-020-04271-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536165PMC
November 2020

Development of a patient-reported outcome questionnaire for aplastic anemia and paroxysmal nocturnal hemoglobinuria (PRO-AA/PNH).

Orphanet J Rare Dis 2020 09 17;15(1):249. Epub 2020 Sep 17.

Division of Hematology, University Hospital Basel, 4031, Basel, Switzerland.

Background: The introduction of new therapy modalities has significantly improved the outcome of aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) patients. However, relatively little is known about the exact disease burden of AA/PNH since standardized assessments of symptoms including health-related quality of life (HRQoL) are frequently missing or inadequately designed for this rare patient group. We aimed to develop AA/PNH-specific questionnaires for self-reporting of symptoms, which could be included in electronic platforms for data collection and patient care.

Methods: By scoping review, we extracted any reported symptoms in AA/PNH and their prevalence from the literature (Phase I). Consensus rounds with patients and medical experts were conducted to identify core symptoms reported in the literature and to add missing items (Phase II). Ultimately, AA/PNH-specific patient-reported outcome (PRO) questionnaires including the selected measures were designed (Phase III).

Results: AA symptoms from 62 and PNH symptoms from 45 observational studies were extracted from the literature. Twenty-four patients and seven medical experts identified 11 core symptoms including HRQoL issues after three consensus rounds. Significant differences in the symptom ranking of patients versus medical experts could be observed. Therefore, patient- as well as expert-centered PRO questionnaires in AA and PNH were created following the concepts of validated instruments.

Conclusion: The development of symptom self-reporting questionnaires for AA and PNH was feasible and the disease-specific PRO questionnaires can now be validated within a web-based workflow in a subsequent feasibility study.
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http://dx.doi.org/10.1186/s13023-020-01532-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495826PMC
September 2020

Long-term outcome of a randomized controlled study in patients with newly diagnosed severe aplastic anemia treated with antithymocyte globulin and cyclosporine, with or without granulocyte colony-stimulating factor: a Severe Aplastic Anemia Working Party Trial from the European Group of Blood and Marrow Transplantation.

Haematologica 2020 05 3;105(5):1223-1231. Epub 2019 Oct 3.

Hemato-Onco-SCT Pole, Hematology Unit. G. Gaslini Children's Research Hospital, Genova, Italy.

This follow-up study of a randomized, prospective trial included 192 patients with newly diagnosed severe aplastic anemia receiving antithymoglobulin and cyclosporine, with or without granulocyte colony-stimulating factor (G-CSF). We aimed to evaluate the long-term effect of G-CSF on overall survival, event-free survival, probability of secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), clinical paroxysmal nocturnal hemoglobinuria, relapse, avascular osteonecrosis and chronic kidney disease. The median follow-up was 11.7 years (95% CI, 10.9-12.5). The overall survival rate at 15 years was 57±12% in the group given G-CSF and 63±12% in the group not given G-CSF (=0.92); the corresponding event-free survival rates were 24±10% and 23±10%, respectively (=0.36). In total, 9 patients developed MDS or AML, 10 only a clonal cytogenetic abnormality, 7 a solid cancer, 18 clinical paroxysmal nocturnal hemoglobinuria, 8 osteonecrosis, and 12 chronic kidney disease, without any difference between patients treated with or without G-CSF. The cumulative incidence of MDS, AML or isolated cytogenetic abnormality at 15 years was 8.5±3% for the G-CSF group and 8.2±3% for the non-G-CSF group (=0.90). The cumulative incidence of any late event including myelodysplastic syndrome or acute myeloid leukemia, isolated cytogenetic abnormalities, solid cancer, clinical paroxysmal nocturnal hemoglobinuria, aseptic osteonecrosis, chronic kidney disease and relapse was 50±12% for the G-CSF group and 49±12% for the non-G-CSF group (=0.65). Our results demonstrate that it is unlikely that G-CSF has an impact on the outcome of severe aplastic anemia; nevertheless, very late events are common and eventually affect the prognosis of these patients, irrespectively of their age at the time of immunosuppressive therapy (NCT01163942).
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http://dx.doi.org/10.3324/haematol.2019.222562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193468PMC
May 2020

Guidelines for Secondary Solid Cancers Among HSCT Recipients-In Reply.

JAMA Oncol 2019 07;5(7):1064-1065

Center for Haematology Imperial College, London, United Kingdom.

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http://dx.doi.org/10.1001/jamaoncol.2019.0636DOI Listing
July 2019

[Bone marrow failure].

Ther Umsch 2019 ;76(9):523-529

Klinik für Hämatologie, Universitätsspital Basel.

Bone marrow failure Bone marrow failure involves a heterogeneous spectrum of rare benign hematological disorders caused by an impaired bone marrow function. Bone marrow failure can be acquired (acquired aplastic anemia) or congenital (inherited bone marrow failures). The disease is clinically characterized by cytopenias of one or more blood cell line (anemia, neutropenia and / or thrombocytopenia), possibly combined with signs of hemolysis and thrombophilia in paroxysmal nocturnal hemoglobinuria or morphological abnormalities in inherited forms. Due to significant advances in molecular genetic diagnostics, a comprehensive differentiation of an acquired or congenital form is central, since the cause of disease significantly affects the choice of therapy. Standard therapy has changed little in past decades (immunosuppression and / or allogeneic stem cell transplantation), however thrombopoietin receptor agonists just recently showed an improvement of all three blood cell lines in acquired aplastic anemia and are likely to be included in the future treatment algorithms. This article gives an overview of the disease, diagnosis and therapy of this heterogeneous disease group.
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http://dx.doi.org/10.1024/0040-5930/a001123DOI Listing
May 2020

Non-GVHD ocular complications after hematopoietic cell transplantation: expert review from the Late Effects and Quality of Life Working Committee of the CIBMTR and Transplant Complications Working Party of the EBMT.

Bone Marrow Transplant 2019 05 27;54(5):648-661. Epub 2019 Feb 27.

Department of Ophthalmology, Hospital Universitario Puerta de Hierro, Madrid, Spain.

Non-graft-vs.-host disease (non-GVHD) ocular complications are generally uncommon after hematopoietic cell transplantation (HCT), but can cause prolonged morbidity affecting activities of daily living and quality of life. Here we provide an expert review of non-GVHD ocular complications in a collaboration between transplant physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Complications discussed in this review include cataracts, glaucoma, ocular infections, ocular involvement with malignancy, ischemic microvascular retinopathy, central retinal vein occlusion, retinal hemorrhage, retinal detachment, and ocular toxicities associated with medications. We have summarized incidence, risk factors, screening, prevention and treatment of individual complicastions and generated evidence-based recommendations. Baseline ocular evaluation before HCT should be considered in all patients who undergo HCT. Follow-up evaluations should be considered according to clinical symptoms, signs and risk factors. Better preventive strategies and treatments remain to be investigated for individual ocular complications after HCT. Both transplant physicians and ophthalmologists should be knowledgeable of non-GVHD ocular complications and provide comprehensive collaborative team care.
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http://dx.doi.org/10.1038/s41409-018-0339-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497536PMC
May 2019

Non-Graft-versus-Host Disease Ocular Complications after Hematopoietic Cell Transplantation: Expert Review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation.

Biol Blood Marrow Transplant 2019 05 3;25(5):e145-e154. Epub 2018 Dec 3.

Department of Ophthalmology, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain.

Non-graft-versus-host disease (GVHD) ocular complications are generally uncommon after hematopoietic cell transplantation (HCT) but can cause prolonged morbidity affecting activities of daily living and quality of life. Here we provide an expert review of non-GVHD ocular complications in a collaboration between transplantation physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Complications discussed in this review include cataracts, glaucoma, ocular infections, ocular involvement with malignancy, ischemic microvascular retinopathy, central retinal vein occlusion, retinal hemorrhage, retinal detachment and ocular toxicities associated with medications. We summarize the incidence, risk factors, screening, prevention, and treatment of individual complications and generate evidence-based recommendations. Baseline ocular evaluation before HCT should be considered in all patients who undergo HCT. Follow-up evaluations should be considered according to clinical signs and symptoms and risk factors. Better preventive strategies and treatments remain to be investigated for individual ocular complications after HCT. Both transplantation physicians and ophthalmologists should be knowledgeable about non-GVHD ocular complications and provide comprehensive collaborative team care.
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http://dx.doi.org/10.1016/j.bbmt.2018.11.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511311PMC
May 2019

Evaluation of Second Solid Cancers After Hematopoietic Stem Cell Transplantation in European Patients.

JAMA Oncol 2019 02;5(2):229-235

Center for Haematology, Imperial College, London, United Kingdom.

Importance: Incidence and risk factors of second solid cancers (SSCs) that occur after hematopoietic stem cell transplantation (HSCT) are well documented. However, clinical outcome data of patients who developed an SSC after HSCT are limited.

Objective: To assess the outcome of patients with an SSC occurring after HSCT from the time of SSC diagnosis.

Design, Setting, And Participants: This cohort study used data of 4065 patients from 26 countries registered with the European Society for Blood and Marrow Transplantation, which has maintained clinical data since 1977 of patients who received a transplant. Information from all patients who underwent a transplant in Europe and had an SSC diagnosis between January 1, 2000, and December 31, 2014, was extracted. The cohort included patients with 18 different cancers. Data analysis was conducted from September 3, 2017, to March 17, 2018.

Main Outcomes And Measures: Median and 5-year age-standardized overall survival, causes of death, risk factor multivariate analysis using a clustered Cox proportional hazard regression model, and standardized mortality ratio were calculated for each of the 18 types of SSC.

Results: In total, 220 617 patients underwent a transplant, of whom only 4065 (1.8%) patients with a second solid cancer after HSCT were included in the study. Among the 4065 patients, 2321 (57.1%) were men and 1744 (42.9%) were women, with a mean (range) age of 59.1 (3.2-82.3) years at diagnosis of second solid cancer. The 5-year age-standardized overall survival was 47% (95% CI, 45%-49%). The 5-year overall survival rate after SSC diagnosis was poor for pancreas, lung, hepatobiliary, esophageal, brain, and gastric cancers, with a median survival between 0.6 and 1 year. The 5-year overall survival was intermediate for endometrial, colorectal, sarcomas, ovarian, bladder, oropharyngeal, and kidney cancers, with a median survival between 2 and 10 years. The 5-year overall survival was more favorable for melanoma, breast, prostate, cervix, and thyroid cancers, with a median survival of 10 or more years. Additional transplant-associated factors for mortality for patients treated with allogeneic HSCT were age at transplant, donor type, conditioning regimen, and graft-vs-host disease. In total, 1777 patients (43.7%) died, of which 1256 (74.8%) were from SSC, 344 (20.5%) from primary disease, and 79 (4.7%) from other causes. Standardized mortality ratio was higher, compared with de novo solid cancers, for melanoma, prostate, breast, kidney, bladder, colorectal, and endometrial cancers but not for the other cancers.

Conclusions And Relevance: The outcome of SSC is mainly dependent on the type of second cancer; thus, future studies should investigate the reasons the standardized mortality ratio is higher for some cancers to identify whether patients with these cancers should be treated differently and to help in screening and counseling patients who developed an SSC after HSCT.
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http://dx.doi.org/10.1001/jamaoncol.2018.4934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439555PMC
February 2019

The future of accreditation of continuing medical education (CME)-continuing professional development (CPD) in Europe: harmonisation through dialogue and consensus.

J Eur CME 2018 3;7(1):1506202. Epub 2018 Sep 3.

Continuing Medical Education - European Accreditors (CME-EA) Registered Association, Cologne, Germany.

In Europe, there are currently some 30 different jurisdictions and no overarching legislation regarding CME-CPD accreditation, since legislative competency related to national health-care systems lies with national authorities. Thus, public demonstration of professional agreement regarding the principles, rules and practice of CME-CPD as well as its accreditation is a highly desirable professional and political objective in Europe, where free movement and freedom to offer professional (medical) services is a key feature of the EU vision of the single market. The newly formed association of independent European accreditors, Continuing Medical Education - European Accreditors (CME-EA) is committed to offering a platform for dialogue between individuals and organisations involved in definition of professional codes in general, and accreditation of CME-CPD in particular on the national level. The aim is to reach a European consensus on principles and rules applied in planning and delivery of CME-CPD. This includes consensus on constituent characteristics of accreditors as well as principles and practice of accreditation.
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http://dx.doi.org/10.1080/21614083.2018.1506202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129779PMC
September 2018

European experience and risk factor analysis of donor cell-derived leukaemias/MDS following haematopoietic cell transplantation.

Leukemia 2019 02 26;33(2):508-517. Epub 2018 Jul 26.

Department of Haematology, Hospital Universitario Puerta de Hierro, Madrid, Spain.

Donor cell leukaemia (DCL) is a rare complication of allogeneic haematopoietic cell transplantation (HCT). We have investigated the prevalence and outcome of donor cell haematology malignancies within centres registered with the European Society of Blood and Marrow transplantation (EBMT). We have sought to identify risk factors to shed light on the pathogenesis of DCL as a model for leukaemogenesis. DCL cases were identified by questionnaire and a follow-up questionnaire requested detailed data. Control subjects from the EBMT registry who had not developed DCL were used for a matched pair analysis to identify risk factors. We identified 38 patients with DCL; the estimated prevalence was 80.5/100,000 transplants. Patients were predominantly treated for haematological malignancy. A clone was retrospectively identified in 7/25 (28%) donors for whom data was available. Overall survival was poor with 29/38 patients dead a median of 11 (range 0-91) months after DCL diagnosis. Matched case-pair analysis identified three factors on multivariate analysis as significantly associated with an increased risk for DCL: use of growth factors within the first 100 days after transplantation, in vivo T-cell depletion and multiple allografts. The risk factors identified, support reduced immune surveillance and replicative stress as pathogenic in the development of DCL.
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http://dx.doi.org/10.1038/s41375-018-0218-6DOI Listing
February 2019

Position paper on current aspects of sponsoring in accredited CME.

J Eur CME 2017 28;6(1):1312062. Epub 2017 Apr 28.

on behalf of the European Board for Accreditation in Cardiology (EBAC), Cologne, Germany.

This position paper is the result of a collaborative approach of several European Specialty Accreditation Boards (ESABs) and, has been stimulated by their current experience in accreditation regarding roles and responsibilities assumed by sponsors of accredited continuing medical education (CME). The suggestions made in this paper aim to preserve the fundamental principle in CME accreditation that the physician in charge of the programme has sole responsibility for the selection of topics, speakers, content and format, as well as mode of presentation, and that sponsors will under no circumstances interfere with this principle. This is considered as a responsibility of an individual physician (or physicians), which cannot be delegated, even in part, to third parties. This responsibility has been extended to include all communication before and after the event. The paper also identifies undecided issues, about which ESABs are committed to elaborate proposals in the future.
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http://dx.doi.org/10.1080/21614083.2017.1312062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843059PMC
April 2017

Does centre experience matter?

Br J Haematol 2017 08 30;178(4):497-498. Epub 2017 May 30.

Haematology and Central Haematology Laboratory, University Hospital of Bern, Bern, Switzerland.

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http://dx.doi.org/10.1111/bjh.14789DOI Listing
August 2017

Hypothyroidism following allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia.

Leuk Res 2017 07 13;58:43-47. Epub 2017 Apr 13.

Endocrinology, Diabetology, and Metabolism, Department of Internal Medicine and Department of Clinical Research, Petersgraben 4, CH-4031 University Hospital Basel, Basel, Switzerland; Department of Endocrinology and Diabetology, Princess Alexandra Hospital, Brisbane, Australia.

Background: Hypothyroidism may complicate allogeneic hematopoietic stem cell transplantation (allo-HSCT); we therefore analyzed risk factors in this study.

Patients And Methods: We studied 229 patients with acute myeloid leukemia (AML) who underwent an allo-HSCT between 2003 and 2013 with different conditioning regimens (myeloablative, reduced-intensity, chemotherapy-based, or total body irradiation-based). Thyroid-stimulating hormone (TSH) and free thyroxine levels (fT4) were available in 104 patients before and after allo-HSCT.

Results: The median age at transplantation (n=104) was 47 (IQR 40-59)], 37 (35.6%) patients were female, and the overall mortality was 34.6% (n=36). After a median follow-up period of 47 (IQR 25-84) months, overt hypothyroidism (basal TSH>4.49mIU/l, FT4<11.6pmol/l) was observed in 4 patients (3.8%) and subclinical hypothyroidism (basal TSH>4.49mIU/l, normal fT4) was observed in 20 patients (19.2%). Positive thyroperoxidase (TPO) antibodies were found in 5 (4.8%) patients. A total of 13 patients (12.5%) were treated with thyroid hormone replacement. Acute graft-versus-host disease (aGvHD) ≥grade 2 occurred in 55 (52.9%) and chronic GvHD (cGvHD) in 74 (71.2%) of the patients. The risk of developing hypothyroidism was higher in the patients with repeated allo-HSCTs (P=0.024) and with positive TPO antibodies (P=0.045). Furthermore, the development of overt hypothyroidism was inversely proportional to age (P=0.043). No correlation was found with GvHD, HLA-mismatch, total body irradiation, and gender.

Conclusion: After allo-HSCT, a significant number of patients experience thyroid dysfunction, including subclinical and overt hypothyroidism. Long-term and continuous follow-up for thyroid function after HSCT is important to provide timely and appropriate treatment.
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http://dx.doi.org/10.1016/j.leukres.2017.04.003DOI Listing
July 2017

Reprint of: Long-Term Survivorship after Hematopoietic Cell Transplantation: Roadmap for Research and Care.

Biol Blood Marrow Transplant 2017 Mar;23(3S):S1-S9

Blood and Marrow Transplant Program, Cleveland Clinic, Cleveland, Ohio.

The number of survivors after hematopoietic cell transplantation (HCT) is expected to dramatically increase over the next decade. Significant and unique challenges confront survivors for decades after their underlying indication (malignancy or marrow failure) has been cured by HCT. The National Institutes of Health (NIH) Late Effects Consensus Conference in June 2016 brought together international experts in the field to plan the next phase of survivorship efforts. Working groups laid out the roadmap for collaborative research and health care delivery. Potentially lethal late effects (cardiac/vascular, subsequent neoplasms, and infectious), patient-centered outcomes, health care delivery, and research methodology are highlighted here. Important recommendations from the NIH Consensus Conference provide fresh perspectives for the future. As HCT evolves into a safer and higher-volume procedure, this marks a time for concerted action to ensure that no survivor is left behind.
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http://dx.doi.org/10.1016/j.bbmt.2017.01.001DOI Listing
March 2017

Long-Term Survivorship after Hematopoietic Cell Transplantation: Roadmap for Research and Care.

Biol Blood Marrow Transplant 2017 Feb 3;23(2):184-192. Epub 2016 Nov 3.

Blood and Marrow Transplant Program, Cleveland Clinic, Cleveland, Ohio.

The number of survivors after hematopoietic cell transplantation (HCT) is expected to dramatically increase over the next decade. Significant and unique challenges confront survivors for decades after their underlying indication (malignancy or marrow failure) has been cured by HCT. The National Institutes of Health (NIH) Late Effects Consensus Conference in June 2016 brought together international experts in the field to plan the next phase of survivorship efforts. Working groups laid out the roadmap for collaborative research and health care delivery. Potentially lethal late effects (cardiac/vascular, subsequent neoplasms, and infectious), patient-centered outcomes, health care delivery, and research methodology are highlighted here. Important recommendations from the NIH Consensus Conference provide fresh perspectives for the future. As HCT evolves into a safer and higher-volume procedure, this marks a time for concerted action to ensure that no survivor is left behind.
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http://dx.doi.org/10.1016/j.bbmt.2016.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237604PMC
February 2017

Similar outcome of upfront-unrelated and matched sibling stem cell transplantation in idiopathic paediatric aplastic anaemia. A study on behalf of the UK Paediatric BMT Working Party, Paediatric Diseases Working Party and Severe Aplastic Anaemia Working Party of EBMT.

Br J Haematol 2015 Nov 28;171(4):585-94. Epub 2015 Jul 28.

Department of Haematology & Bone Marrow Transplantation, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

We explored the feasibility of unrelated donor haematopoietic stem cell transplant (HSCT) upfront without prior immunosuppressive therapy (IST) in paediatric idiopathic severe aplastic anaemia (SAA). This cohort was then compared to matched historical controls who had undergone first-line therapy with a matched sibling/family donor (MSD) HSCT (n = 87) or IST with horse antithymocyte globulin and ciclosporin (n = 58) or second-line therapy with unrelated donor HSCT post-failed IST (n = 24). The 2-year overall survival in the upfront cohort was 96 ± 4% compared to 91 ± 3% in the MSD controls (P = 0·30) and 94 ± 3% in the IST controls (P = 0·68) and 74 ± 9% in the unrelated donor HSCT post-IST failure controls (P = 0·02).The 2-year event-free survival in the upfront cohort was 92 ± 5% compared to 87 ± 4% in MSD controls (P = 0·37), 40 ± 7% in IST controls (P = 0·0001) and 74 ± 9% in the unrelated donor HSCT post-IST failure controls (n = 24) (P = 0·02). Outcomes for upfront-unrelated donor HSCT in paediatric idiopathic SAA were similar to MSD HSCT and superior to IST and unrelated donor HSCT post-IST failure. Front-line therapy with matched unrelated donor HSCT is a novel treatment approach and could be considered as first-line therapy in selected paediatric patients who lack a MSD.
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http://dx.doi.org/10.1111/bjh.13614DOI Listing
November 2015

Temperature-Sensitive Indicators for Monitoring RBC Concentrates Out of Controlled Temperature Storage.

Am J Clin Pathol 2015 Jul;144(1):145-50

From the Blood Transfusion Center beider Basel, Swiss Red Cross, Basel, Switzerland;

Objectives: The 30-minute rule for RBC concentrates out of controlled temperature storage does not take into account multiple parameters that influence warming of RBC concentrates. This study evaluated two temperature-sensitive indicators (TIs) for monitoring RBC concentrates during transport.

Methods: TI labels (Check-Spot [Harald H. Temmel KG, Gleisdorf, Austria] and Thermoindikator V4 [BASF, Basel, Switzerland]) were attached to RBC concentrates prior to delivery. Duration of transport, ambient temperatures, and label results (valid vs expired) were recorded. We evaluated the proportion of labels discrepant to the 30-minute rule overall and among deliveries 30 minutes or less and more than 30 minutes and compared the rates of valid and expired readings between both TIs.

Results: In total, 201 RBC concentrate deliveries (86.6%) lasted 30 minutes or less, and 31 (13.4%) were more than 30 minutes. Forty-six (19.8%) Check-Spot and 37 (15.9%) Thermoindikator V4 results were discrepant to the 30-minute rule. Sixteen (51.6%) and 27 (87.1%) RBC concentrate deliveries more than 30 minutes displayed valid label readings with Check-Spot and Thermoindikator V4, respectively. Rates of expired labels among deliveries 30 minutes or less and valid labels among deliveries more than 30 minutes differed significantly between TIs (P < .01).

Conclusions: TIs identified a considerable number of RBC concentrates whose temperatures may not be adequately reflected by the 30-minute rule. Variability of readings between TIs stresses the necessity of validation prior to implementation.
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http://dx.doi.org/10.1309/AJCPN7L9RTTPNNRWDOI Listing
July 2015

Find-A-Code: how accurate is the international classification of diseases coding system for aplastic anemia?

Eur J Haematol 2015 May;94(5):377-8

Department of Hematology, University Hospital Basel, Basel, Switzerland.

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http://dx.doi.org/10.1111/ejh.12461DOI Listing
May 2015

Outcome of aplastic anaemia in children. A study by the severe aplastic anaemia and paediatric disease working parties of the European group blood and bone marrow transplant.

Br J Haematol 2015 May 14;169(4):565-73. Epub 2015 Feb 14.

Clinical and Experimental Haematology Unit, G Gaslini Childrens' Hospital, Genova, Italy.

This study analysed the outcome of 563 Aplastic Anaemia (AA) children aged 0-12 years reported to the Severe Aplastic Anaemia Working Party database of the European Society for Blood and Marrow Transplantation, according to treatment received. Overall survival (OS) after upfront human leucocyte antigen-matched family donor (MFD) haematopoietic stem cell transplantation (HSCT) or immunosuppressive treatment (IST) was 91% vs. 87% (P 0·18). Event-free survival (EFS) after upfront MFD HSCT or IST was 87% vs. 33% (P 0·001). Ninety-one of 167 patients (55%) failed front-line IST and underwent rescue HSCT. The OS of this rescue group was 83% compared with 91% for upfront MFD HSCT patients and 97% for those who did not fail IST up-front (P 0·017). Rejection was 2% for MFD HSCT and HSCT post-IST failure (P 0·73). Acute graft-versus-host disease (GVHD) grade II-IV was 8% in MFD graft vs. 25% for HSCT post-IST failure (P < 0·0001). Chronic GVHD was 6% in MFD HSCT vs. 20% in HSCT post-IST failure (P < 0·0001). MFD HSCT is an excellent therapy for children with AA. IST has a high failure rate, but remains a reasonable first-line choice if MFD HSCT is not available because high OS enables access to HSCT, which is a very good rescue option.
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http://dx.doi.org/10.1111/bjh.13297DOI Listing
May 2015

Survivorship after allogeneic transplantation-management recommendations for the primary care provider.

Curr Hematol Malig Rep 2015 Mar;10(1):35-44

Division of Hematology, University Hospital of Basel, Petersgraben 4, 4031, Basel, Switzerland,

Prognosis after allogeneic hematopoietic stem cell transplantation (HSCT) has greatly improved. Therefore, long-term survivorship becomes an important issue. A number of malignant and nonmalignant late effects can cause substantial morbidity, with considerable impact on health and quality of life. The main factors responsible for late effects after HSCT are total body irradiation-based conditioning and chronic graft-versus-host disease and its treatment. The knowledge on late effects serves as guidance for surveillance and management decision. Aftercare includes screening and counseling for prevention and treatment of late complications. The care of HSCT recipients tends with time to be transferred from the transplant center back to the primary care provider, who might not be however familiar with the unique needs of long-term survivors. A broad expertise is needed for the post-transplant management; therefore, transplant centers together with primary care providers should ensure complementary care delivery. Standardized follow-up guidelines on late effects represent the best tool to guaranty good management of long-term survivors. Distribution, broad promotion, and applications of these guidelines are therefore needed.
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http://dx.doi.org/10.1007/s11899-014-0243-0DOI Listing
March 2015

Outcome of aplastic anemia in adolescence: a survey of the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation.

Haematologica 2014 Oct 1;99(10):1574-81. Epub 2014 Aug 1.

Department of Haematological Medicine, King's College Hospital/King's College London, UK.

We analyzed the outcome of 537 adolescents (age 12-18 years) with idiopathic aplastic anemia included in the database of the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation comparing: i) matched family donor hematopoietic stem cell transplantation performed as first-line treatment with ii) front-line immunosuppressive therapy not followed by subsequent transplant given for failure and with iii) hematopoietic stem cell transplantation performed after failed front-line immunosuppressive therapy. Overall survival was 86% in the matched family donor hematopoietic stem cell transplantation group, 90% in patients given front-line immunosuppressive alone (those who did not fail this treatment and who did not receive subsequent rescue with hematopoietic stem cell transplantation) and 78% in subjects who underwent hematopoietic stem cell transplantation post failed front-line immunosuppressive therapy (P=0.14). Event-free survival in the same groups was respectively 83%, 64% and 71% (P=0.04). Cumulative incidence of rejection was 8% in matched family donor hematopoietic stem cell transplantation and 9% in transplants post failed front-line immunosuppression (P=0.62). Cumulative incidence of acute graft-versus-host disease was 12% in matched family donor transplants and 18% in transplants post failed immunosuppression (P=0.18). Chronic graft-versus-host disease was higher in matched family donor hematopoietic stem cell transplantation (8%) than in transplants post failed immunosuppressive therapy (20%) (P=0.0009). Cumulative incidence of post-therapy malignancies was 0.7% in matched family donor transplantations, 7% in transplantations post failed immunosuppression and 21% after front-line immunosuppression (P=0.0017). In the whole cohort, under multivariate analysis, the diagnosis to treatment interval of two months or under positively affected overall survival whereas up-front immunosuppression alone (with no subsequent rescue transplants) negatively affected event-free survival. In transplanted patients an interval from diagnosis to treatment of 2 months or under, bone marrow as source of cells and first-line matched family donor transplants provided a significant advantage in overall and event-free survival. Aplastic anemia in adolescents has a very good outcome. If a matched family donor is available, hematopoietic stem cell transplantation using bone marrow cells is the first choice treatment. If such a donor is not available, immunosuppressive treatment may still be an acceptable second choice, also because, in case of failure, hematopoietic stem cell transplantation is a very good rescue option.
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http://dx.doi.org/10.3324/haematol.2014.106096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181253PMC
October 2014

Lost in transition: the essential need for long-term follow-up clinic for blood and marrow transplantation survivors.

Biol Blood Marrow Transplant 2015 Feb 3;21(2):225-32. Epub 2014 Jul 3.

Division of Hematology/Oncology, Vanderbilt University, Nashville, Tennessee.

Because of expanding indications and improvements in supportive care, the utilization of blood and marrow cell transplantation (BMT) to treat various conditions is increasing exponentially, and currently more than 60,000 BMTs are performed annually worldwide. By the year 2030, it is projected that the number of BMT survivors will increase 5-fold, potentially resulting in one half of a million survivors in the United States alone. As the majority of survivors now live beyond the first 2 years after BMT, they are prone to a unique set of complications and late effects. Until recently, BMT experts assumed responsibility for almost all of the care for these survivors, but now oncologists/hematologists, pediatricians, and internists are involved frequently in offering specialized care and preventive services to these survivors. To integrate and translate into clinical practice the unique BMT survivorship issues with current preventive guidelines, a team effort is required. This can be facilitated by a dedicated "long-term-follow-up (LTFU)" clinic that provides lifelong care for BMT survivors. In this review, we first illustrate with clinical vignettes the need for LTFU and then focus upon the following: (1) types of LTFU clinic models, (2) challenges and possible solutions to the establishment of LTFU clinic, and (3) vulnerable transition periods.
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http://dx.doi.org/10.1016/j.bbmt.2014.06.035DOI Listing
February 2015

[Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation].

Rinsho Ketsueki 2014 Jun;55(6):607-32

National Marrow Donor Program.

Advances in hematopoietic cell transplantation (HCT) technology and supportive care techniques have led to improvements in long-term survival after HCT. Emerging indications for transplantation, introduction of newer graft sources (eg, umbilical cord blood) and transplantation of older patients using less intense conditioning regimens have also contributed to an increase in the number of HCT survivors. These survivors are at risk for developing late complications secondary to pre-, peri-, and posttransplantation exposures and risk factors. Guidelines for screening and preventive practices for HCT survivors were published in 2006. An international group of transplantation experts was convened in 2011 to review contemporary literature and update the recommendations while considering the changing practice of transplantation and international applicability of these guidelines. This review provides the updated recommendations for screening and preventive practices for pediatric and adult survivors of autologous and allogeneic HCT.
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June 2014

Outcome of allogeneic stem cell transplantation for patients transformed to myelodysplastic syndrome or leukemia from severe aplastic anemia: a report from the MDS Subcommittee of the Chronic Malignancies Working Party and the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation.

Biol Blood Marrow Transplant 2014 Sep 6;20(9):1448-50. Epub 2014 Jun 6.

Bone Marrow Transplantation Center, University Hospital Eppendorf, Hamburg, Germany.

One hundred and forty patients who had undergone hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) transformation after treatment of severe aplastic anemia (SAA) were identified in the European Group for Blood and Marrow Transplantation (EBMT) database. The median age at HSCT was 29 years (range, 1 to 66 years). The transplant donor was related in 49% cases and unrelated in 51% cases. The 5-year probability of relapse was 17%, and that of nonrelapse mortality was 41%. The 5-year overall survival was 45% ± 9%, better for patients untreated and patients in remission compared with patients with refractory disease. Our data indicate that allogeneic HSCT leads to prolonged survival in close to one-half of the patients transforming to MDS or AML from SAA.
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http://dx.doi.org/10.1016/j.bbmt.2014.05.028DOI Listing
September 2014