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  • Halaburda, Kazimierz; Labopin, Myriam; Houhou, Mohamed; Niederwieser, Dietger; Finke, Juergen; Volin, Liisa; Maertens, Johan; Cornelissen, Jan J.; Milpied, Noel; Stuhler, Gernot; Kroeger, Nicolaus; Esteve, Jordi; Mohty, Mohamad; Nagler, Arnon (2018)
    Acute myeloid leukemia with inv(3)(q21;q26.2)/t(3;3)(q21;q26.2) (3q26 AML) is a rare disease with poor prognosis and median survival of
  • Robin, Marie; Chevret, Sylvie; Koster, Linda; Wolschke, Christine; Yakoub-Agha, Ibrahim; Bourhis, Jean Henri; Chevallier, Patrice; Cornelissen, Jan J.; Remenyi, Peter; Maertens, Johan; Poire, Xavier; Craddock, Charles; Socie, Gerard; Itälä-Remes, Maija; Schouten, Harry C.; Marchand, Tony; Passweg, Jakob; Blaise, Didier; Damaj, Gandhi; Ozkurt, Zubeyde Nur; Zuckerman, Tsila; Cluzeau, Thomas; Labussiere-Wallet, Helene; Cammenga, Jörg; McLornan, Donal; Chalandon, Yves; Kroger, Nicolaus (2019)
    The use of antihuman T-lymphocyte immunoglobulin in the setting of transplantation from an HLA-matched related donor is still much debated. Acute and chronic graft-versus-host disease are the main causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis. The aim of this study was to evaluate the effect of antihuman T-lymphocyte immunoglobulin in a large cohort of patients with myelofibrosis (n= 287). The cumulative incidences of grade II-IV acute graft-versus-host disease among patients who were or were not given antihuman T-lymphocyte immunoglobulin were 26% and 41%, respectively. The corresponding incidences of chronic graft-versus-host disease were 52% and 55%, respectively. Non-adjusted overall survival, disease-free survival and non-relapse mortality rates were 55% versus 53%, 49% versus 45%, and 32% versus 31%, respectively, among the patients who were or were not given antihuman T-lymphocyte immunoglobulin. An adjusted model confirmed that the risk of acute graft-versus-host disease was lower following antihuman T-lymphocyte immunoglobulin (hazard ratio, 0.54; P= 0.010) while it did not decrease the risk of chronic graft-versus-host disease. The hazard ratios for overall survival and non-relapse mortality were 0.66 and 0.64, with P-values of 0.05 and 0.09, respectively. Antihuman T-lymphocyte immunoglobulin did not influence disease-free survival, graft-versus-host disease, relapse-free survival or relapse risk. In conclusion, in the setting of matched related transplantation in myelofibrosis patients, this study demonstrates that antihuman T-lymphocyte immunoglobulin decreases the risk of acute graft-versushost disease without increasing the risk of relapse.
  • Turunen, Antti; Partanen, Anu; Valtola, Jaakko; Ropponen, Antti; Siitonen, Timo; Kuittinen, Outi; Kuitunen, Hanne; Putkonen, Mervi; Sankelo, Marja; Keskinen, Leena; Savolainen, Eeva-Riitta; Pyörälä, Marja; Kuittinen, Taru; Silvennoinen, Raija; Penttilä, Karri; Sikiö, Anu; Vasala, Kaija; Mäntymaa, Pentti; Pelkonen, Jukka; Varmavuo, Ville; Jantunen, Esa (2020)
    BACKGROUND Autologous stem cell transplantation is an established treatment option for patients with multiple myeloma (MM) or non-Hodgkin?s lymphoma (NHL). STUDY DESIGN AND METHODS In this prospective multicenter study, 147 patients with MM were compared with 136 patients with NHL regarding the mobilization and apheresis of blood CD34+ cells, cellular composition of infused blood grafts, posttransplant recovery, and outcome. RESULTS Multiple myeloma patients mobilized CD34+ cells more effectively (6.3???106/kg vs. 3.9???106/kg, p?=?0.001). The proportion of poor mobilizers (peak blood CD34+ cell count 100?days) nonrelapse mortality (NRM; 6% vs. 0%, p?=?0.003). CONCLUSIONS Non-Hodgkin?s lymphoma and MM patients differ in terms of mobilization of CD34+ cells, graft cellular composition, and posttransplant recovery. Thus, the optimal graft characteristics may also be different.
  • Kreutzman, Anna; Rohon, Peter; Faber, Edgar; Indrak, Karel; Juvonen, Vesa; Kairisto, Veli; Voglova, Jaroslava; Sinisalo, Marjatta; Flochova, Emilia; Vakkila, Jukka; Arstila, Petteri; Porkka, Kimmo; Mustjoki, Satu (2011)
  • Rolfes, M. C.; Sriaroon, P.; Saldana, B. J. Davila; Dvorak, C. C.; Chapdelaine, H.; Ferdman, R. M.; Chen, K.; Jolles, S.; Patel, N. C.; Kim, Y. J.; Tarrant, T. K.; Martelius, T.; Seppanen, M.; Joshi, A. Y. (2019)
    Objective: Predictive factors associated with clinical outcomes of chronic norovirus infection (CNI) in primary immunodeficiency diseases (PIDD) are lacking. Method: We sought to characterize CNI using a multi-institutional cohort of patients with PIDD and CNI using the Clinical Immunology Society's CIS-PIDD Listserv e-mail group. Results: Thirty-four subjects (21 males and 13 females) were reported from centers across North America, Europe, and Asia. All subjects were receiving high doses (median IgG dose: 1200 mg/kg/month) of supplemental immunoglobulin therapy. Fifty-three percent had a complete absence of B cells (median B-cell count 0; range 0-139 cells/mu L). Common Variable Immune Deficiency (CVID) subjects manifested a unique phenotype with B-cell lymphopenia, non O+ blood type, and villous atrophy (logistic regression model, P = 0.01). Five subjects died, all of whom had no evidence of villous atrophy. Conclusion: While Norovirus (NoV) is thought to replicate in B cells, in this PIDD cohort of CNI, B-cell lymphopenia was common, indicating that the presence of B lymphocytes is not essential for CNI. (C) 2018 Published by Elsevier Inc.
  • Toppila, Iiro; Kysenius, Kai; Miettinen, Tatu; Lassenius, Mariann Ida; Lievonen, Juha; Anttila, Pekka (2022)
    Multiple myeloma (MM) patients are predominantly elderly with comorbidities that have an impact on patient mortality and treatment decisions. We previously reported the patient characteristics and overall survival outcomes of the Finnish MM cohort diagnosed between 2005 and 2016 in a nationwide retrospective registry study comprising 3,851 adults. Here, we report detailed comorbidity characteristics for this real-world Finnish MM population at cohort entry and during follow-up. Data on diagnoses and causes of death were obtained from Finnish healthcare data registries and interrogated using various multistate time-to-event models. In the year preceding MM diagnosis, comorbidities (as per Charlson Comorbidity Index definition) were recorded in 38.0% of the cohort, of which 27.9% presented with pre-existing cardiovascular disease (CVD) and 4.8% had suffered a major adverse cardiac event (MACE). At 2 years post-MM diagnosis, cumulative incidence for CVD and MACE more than doubled to 57.1% and 11.4%, respectively, and only 31.9% of the cohort remained CVD-free. Prevalent secondary malignancies were recorded in 16.8% of the patient population at MM diagnosis, with cumulative incidence increasing steadily to 27.5% at 2 years and 33% at 5 years post-diagnosis. The main cause of mortality attributed to MM, CVD, secondary malignancy, or other causes remained stable throughout the follow-up, at an average of 74.2%, 9.4%, 9.8%, and 6.5%, respectively. Prevalence of CVDs and secondary malignancies is high in Finnish patients at MM diagnosis, with older male patients suffering from higher MACE and mortality risk. Proper recording and management of comorbidities alongside novel treatments remain crucial for optimal MM management.
  • Corbacioglu, Selim; Carreras, Enric; Mohty, Mohamad; Pagliuca, Antonio; Boelens, Jaap Jan; Damaj, Gandhi; Iacobelli, Massimo; Niederwieser, Dietger; Olavarria, Eduardo; Suarez, Felipe; Ruutu, Tapani; Verdonck, Leo; Hume, Robin; Nejadnik, Bijan; Lai, Chinglin; Finetto, Giorgia; Richardson, Paul (2016)
    Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable and potentially fatal complication of hematopoietic cell transplantation (HCT) or nontransplantation-associated chemotherapy/radiotherapy. In cases of severe hepatic VOD/SOS, typically defined by associated multiorgan failure (MOF, also known as multiorgan dysfunction), mortality exceeds 80%. Preclinical and early clinical data have provided a rationale for defibrotide treatment in hepatic VOD/SOS. Based on this evidence and in recognition of the dismal prognosis for these patients, defibrotide was made available through an international multicenter compassionate-use program conducted from December 1998 to March 2009. Physicians participating in the program voluntarily provided demographic and outcome data for patients given defibrotide. Efficacy and safety analyses were performed using the data received for 710 treated patients. Defibrotide was given at 10, 25, 40, 60, or 80 mg/kg/day for a median of 15 days (range, 1 to 119 days). By Kaplan-Meier analysis, the estimated overall day +100 survival was 54% (58% in the 25 mg/kg/day dose group). Adverse events (AEs) were reported in 53% of patients. The most common AEs were MOF, progression of hepatic VOD/SOS, sepsis, and graft-versus-host disease, which were consistent with the AEs expected for this patient population. No clinically meaningful trends in AEs were identified by gender, age, or dose group. Safety and efficacy results were consistent with prior studies of defibrotide in hepatic VOD/SOS, and subgroup analyses lend support to the use of the 25 mg/kg/day dose. (C) 2016 American Society for Blood and Marrow Transplantation.
  • Corbacioglu, S.; Carreras, E.; Ansari, M.; Balduzzi, A.; Cesaro, S.; Dalle, J-H; Dignan, F.; Gibson, B.; Guengoer, T.; Gruhn, B.; Lankester, A.; Locatelli, F.; Pagliuca, A.; Peters, C.; Richardson, P. G.; Schulz, A. S.; Sedlacek, P.; Stein, J.; Sykora, K-W; Toporski, J.; Trigoso, E.; Vetteranta, K.; Wachowiak, J.; Wallhult, E.; Wynn, R.; Yaniv, I.; Yesilipek, A.; Mohty, M.; Bader, P. (2018)
    The advances in hematopoietic cell transplantation (HCT) over the last decade have led to a transplant-related mortality below 15%. Hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a life-threatening complication of HCT that belongs to a group of diseases increasingly identified as transplant-related, systemic endothelial diseases. In most cases, SOS/VOD resolves within weeks; however, severe SOS/VOD results in multi-organ dysfunction/failure with a mortality rate > 80%. A timely diagnosis of SOS/VOD is of critical importance, given the availability of therapeutic options with favorable tolerability. Current diagnostic criteria are used for adults and children. However, over the last decade it has become clear that SOS/VOD is significantly different between the age groups in terms of incidence, genetic predisposition, clinical presentation, prevention, treatment and outcome. Improved understanding of SOS/VOD and the availability of effective treatment questions the use of the Baltimore and Seattle criteria for diagnosing SOS/VOD in children. The aim of this position paper is to propose new diagnostic and severity criteria for SOS/VOD in children on behalf of the European Society for Blood and Marrow Transplantation.
  • European Soc Blood Marrow Transpla; HOVON-SAKK (2018)
    Background. Disease recurrence remains the major cause of death in adults with acute myeloid leukaemia (AML) treated using either intensive chemotherapy (IC) or allogenic stem cell transplantation (allo-SCT). Aims. The timely delivery of maintenance drug or cellular therapies represent emerging strategies with the potential to reduce relapse after both treatment modalities, but whilst the determinants of overall relapse risk have been extensively characterized the factors determining the timing of disease recurrence have not been characterized. Materials and Methods. We have therefore examined, using a series of sequential landmark analyses, relapse kinetics in a cohort of 2028 patients who received an allo-SCT for AML in CR1 and separately 570 patients treated with IC alone. Results. In the first 3 months after allo-SCT, the factors associated with an increased risk of relapse included the presence of the FLT3-ITD (P <0.001), patient age (P = 0.012), time interval from CR1 to transplant (P <0.001) and donor type (P = 0.03). Relapse from 3 to 6 months was associated with a higher white cell count at diagnosis (P = 0.001), adverse-risk cytogenetics (P <0.001), presence of FLT3-ITD mutation (P <0.001) and time interval to achieve first complete remission (P = 0.013). Later relapse was associated with adverse cytogenetics, mutated NPM1, absence of chronic graft-versus-host disease (GVHD) and the use of in vivo T-cell depletion. In patients treated with IC alone, the factors associated with relapse in the first 3 months were adverse-risk cytogenetics (P <0.001) and FLT3-ITD status (P = 0.001). The factors predicting later relapse were the time interval from diagnosis to CR1 (P = 0.22) and time interval from CR1 to IC (P = 0.012). Discussion and Conclusion. Taken together, these data provide novel insights into the biology of disease recurrence after both allo-SCT and IC and have the potential to inform the design of novel maintenance strategies in both clinical settings.
  • Kiesewetter, Barbara; Cherny, Nathan I.; Boissel, Nicolas; Cerisoli, Francesco; Dafni, Urania; de Vries, Elisabeth G. E.; Ghia, Paolo; Goekbuget, Nicola; Gonzalez-Calle, Veronica; Huntly, Brian; Jaeger, Ulrich; Latino, Nicola Jane; Douillard, Jean-Yves; Malcovati, Luca; Mateos, Maria-Victoria; Ossenkoppele, Gert J.; Porkka, Kimmo; Raderer, Markus; Ribera, Josep-Maria; Scarfo, Lydia; Wester, Ruth; Zygoura, Panagiota; Sonneveld, Pieter (2020)
    Objective Value frameworks in oncology have not been validated for the assessment of treatments in haematological malignancies, but to avoid overlaps and duplications it appears reasonable to build up experience on existing value frameworks, such as the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). Methods Here we present the results of the first feasibility testing of the ESMO-MCBS v1.1 for haematological malignancies based on the grading of 80 contemporary studies for acute leukaemia, chronic leukaemia, lymphoma, myeloma and myelodysplastic syndromes. The aims were (1) to evaluate the scorability of data, (2) to evaluate the reasonableness of the generated grades for clinical benefit using the current version and (3) to identify shortcomings in the ESMO-MCBS v1.1 that require amendments to improve the efficacy and validity of the scale in grading new treatments in the management of haematological malignancies. Results In general, the ESMO-MCBS v1.1 was found to be widely applicable to studies in haematological malignancies, generating scores that were judged as reasonable by European Hematology Association (EHA) experts. A small number of studies could either not be graded or were not appropriately graded. The reasons, related to the differences between haematological and solid tumour malignancies, are identified and described. Conclusions Based on the findings of this study, ESMO and EHA are committed to develop a version of the ESMO-MCBS that is validated for haematological malignancies. This development process will incorporate all of the usual stringencies for accountability of reasonableness that have characterised the development of the ESMO-MCBS including field testing, statistical modelling, evaluation for reasonableness and openness to appeal and revision. Applying such a scale will support future public policy decision-making regarding the value of new treatments for haematological malignancies and will provide insights that could be helpful in the design of future clinical trials.
  • Sullivan, Kathleen E.; Bassiri, Hamid; Bousfiha, Ahmed A.; Costa-Carvalho, Beatriz T.; Freeman, Alexandra F.; Hagin, David; Lau, Yu L.; Lionakis, Michail S.; Moreira, Ileana; Pinto, Jorge A.; de Moraes-Pinto, M. Isabel; Rawat, Amit; Reda, Shereen M.; Lugo Reyes, Saul Oswaldo; Seppanen, Mikko; Tang, Mimi L. K. (2017)
    In today's global economy and affordable vacation travel, it is increasingly important that visitors to another country and their physician be familiar with emerging infections, infections unique to a specific geographic region, and risks related to the process of travel. This is never more important than for patients with primary immunodeficiency disorders (PIDD). A recent review addressing common causes of fever in travelers provides important information for the general population Thwaites and Day (N Engl J Med 376:548-560, 2017). This review covers critical infectious and management concerns specifically related to travel for patients with PIDD. This review will discuss the context of the changing landscape of infections, highlight specific infections of concern, and profile distinct infection phenotypes in patients who are immune compromised. The organization of this review will address the environment driving emerging infections and several concerns unique to patients with PIDD. The first section addresses general considerations, the second section profiles specific infections organized according to mechanism of transmission, and the third section focuses on unique phenotypes and unique susceptibilities in patients with PIDDs. This review does not address most parasitic diseases. Reference tables provide easily accessible information on a broader range of infections than is described in the text.
  • Brodszki, Nicholas; Frazer-Abel, Ashley; Grumach, Anete S.; Kirschfink, Michael; Litzman, Jiri; Perez, Elena; Seppänen, Mikko R. J.; Sullivan, Kathleen E.; Jolles, Stephen (2020)
    This guideline aims to describe the complement system and the functions of the constituent pathways, with particular focus on primary immunodeficiencies (PIDs) and their diagnosis and management. The complement system is a crucial part of the innate immune system, with multiple membrane-bound and soluble components. There are three distinct enzymatic cascade pathways within the complement system, the classical, alternative and lectin pathways, which converge with the cleavage of central C3. Complement deficiencies account for similar to 5% of PIDs. The clinical consequences of inherited defects in the complement system are protean and include increased susceptibility to infection, autoimmune diseases (e.g., systemic lupus erythematosus), age-related macular degeneration, renal disorders (e.g., atypical hemolytic uremic syndrome) and angioedema. Modern complement analysis allows an in-depth insight into the functional and molecular basis of nearly all complement deficiencies. However, therapeutic options remain relatively limited for the majority of complement deficiencies with the exception of hereditary angioedema and inhibition of an overactivated complement system in regulation defects. Current management strategies for complement disorders associated with infection include education, family testing, vaccinations, antibiotics and emergency planning.
  • Hyvarinen, Kati; Ritari, Jarmo; Koskela, Satu; Niittyvuopio, Riitta; Nihtinen, Anne; Volin, Liisa; Gallardo, David; Partanen, Jukka (2017)
    Despite detailed human leukocyte antigen (HLA) matching and modern immunosuppressive therapy, severe graft-versus-host disease (GvHD) remains a major hurdle for successful allogeneic hematopoietic stem cell transplantation (HSCT). As the genetic diversity in GvHD complicates the systematic discovery of associated variants across populations, we studied 122 GvHD-associated single nucleotide polymorphisms (SNPs) in 492 HLA-matched sibling HSCT donor-recipient pairs from Finland and Spain. The association between these candidate SNPs and grade III-IV acute GvHD and extensive chronic GvHD was assessed. The functional effects of the variants were determined using expression and cytokine quantitative trait loci (QTL) database analyses. Clear heterogeneity was observed in the associated markers between the two populations. Interestingly, the majority of markers, such as those annotated to IL1, IL23R, TLR9, TNF, and NOD2 genes, are related to the immunological response by monocytes-macrophages to microbes, a step that precedes GvHD as a result of intestinal lesions. Furthermore, cytokine QTL analysis showed that the GvHD-associated markers regulate IL1 beta, IFN gamma, and IL6 responses. These results support a crucial role for the anti-microbial response in GvHD risk. Furthermore, despite apparent heterogeneity in the genetic markers associated with GvHD, it was possible to identify a biological pathway shared by most markers in both populations.
  • Kero, A. E.; Madanat-Harjuoja, L. M.; Jarvela, L. S.; Malila, N.; Matomaki, J.; Lahteenmaki, P. M. (2016)
    Purpose: Childhood cancer survivors are at risk for developing metabolic syndrome (MetS), which subsequently leads to cardiovascular morbidity and excess mortality. Our aim was to investigate the purchases of medications associated with MetS among 7551 early onset cancer patients compared to siblings. Methods: Our nationwide Finnish population-based registry study analyzed the drug purchase of medication among early onset cancer patients diagnosed with cancer below the age of 35 years between 1994 and 2004 compared to siblings by linkage to the drug purchase registry, allowing for a maximal follow-up of 18 years. Results: The hazard ratios (HRs) for purchasing antihypertensives and diabetes drugs were higher after both childhood (HR 4.6, 95% CI 3.1-7.0; HR 3.0, 95% 1.5-6.1) and young adulthood (YA) cancer (HR 1.5, 95% CI 1.3-1.8; HR 1.6, 95% CI 1.1-2.2) compared to siblings. The HRs for purchasing lipid-lowering drugs were elevated both after childhood (HR 4.3,95% CI 0.9-19.5) and YA cancer (HR 1.6, 95% CI 1.04-2.5), but only reached significance in YA cancer patients. Among specific cancer diagnosis groups, highest HR values for antihypertensives were found in childhood acute lymphoblastic leukemia (ALL) (HR 6.1, 95% CI 3.7-10.3) and bone tumor (HR 4.3, 95% CI 1.9-9.4), and YA ALL (HR 4.8, 95% CI 3.1-7.0) and acute myeloid leukemia (AML) (HR 3.4, 95% CI 2.5-5.1) patients. Moreover, childhood ALL (HR 6.3, 95% CI 2.7-14.8), AML (HR 7.6, 95% CI 1.9-24.5) and central nervous system (CNS)-tumor (HR 3.5, 95% CI 1.3-9.2) and YA ALL (HR 3.7, 95% CI 1.2-9.5) patients showed the strongest likelihood of purchasing diabetes drugs compared to siblings. Conclusion: The purchase of medications associated with MetS was increased after early onset cancer and highly dependent on the age at cancer diagnosis and the cancer diagnosis. Prevention strategies are imperative for reducing potentially life-threatening cardiovascular complications after early onset cancer. (C) 2016 Elsevier Ltd. All rights reserved.
  • McCaughan, Georgia J.; Gandolfi, Sara; Moore, John J.; Richardson, Paul G. (2022)
    For patients with newly diagnosed multiple myeloma, survival outcomes continue to improve significantly: however, nearly all patients will relapse following induction treatment. Optimisation of induction therapy is essential to provide longer term disease control and the current standard of care for most patients incorporates an immunomodulatory agent and proteasome inhibitor, most commonly lenalidomide and bortezomib in combination with dexamethasone (RVD), with maintenance until progression. Historically there has been limited access to RVD as an induction strategy outside of the United States; fortunately, there is now increasing access worldwide. This review discusses the rationale for use of RVD as induction therapy and aims to provide guidance in prescribing this regimen in order to optimise efficacy while minimising the toxicities of treatment. We also highlight the increasing evidence for the utility of addition of a monoclonal antibody to the RVD backbone to deepen responses and potentially provide longer disease control.
  • Pagliuca, Simona; de Latour, Regis Peffault; Volt, Fernanda; Locatelli, Franco; Zecca, Marco; Dalle, Jean-Hugues; Comoli, Patrizia; Vettenranta, Kim; Angel Diaz, Miguel; Reuven, Or; Bertrand, Yves; Diaz de Heredia, Cristina; Nagler, Arnon; Ghavamzadeh, Ardeshir; Sufliarska, Sabina; Lawson, Sarah; Kenzey, Chantal; Rocha, Vanderson; Dufour, Carlo; Gluckman, Eliane; Passweg, Jakob; Ruggeri, Annalisa (2017)
    Cord blood transplantation (CBT) from HLA-identical siblings is an attractive option for patients with bone marrow failure (BMF) syndrome because of the low risk of graft-versus-host disease (GVHD) and the absence of risk to the donor. We analyzed outcomes of 117 patients with inherited or acquired BMF syndrome who received CBT from a related HLA-identical donor in European Society for Blood and Marrow Transplantation centers between 1988 and 2014. Ninety-seven patients had inherited and 20 patients acquired BMF syndrome. Eighty-two patients received a single cord blood (CB) unit, whereas 35 patients received a combination of CB and bone marrow cells from the same donor. Median age at CBT was 6.7 years, and median follow-up was 86.7 months. The cumulative incidence function (CIF) of neutrophil recovery was 88.8% (95% CI, 83.1% to 94.9%), 100-day CIF of grades II to IV acute GVHD was 15.2%, and 7-year CIF of chronic GVHD was 14.5%. Overall survival at 7 years was 87.9% (95% CI, 80.8% to 92.6%), 89% for inherited and 81% for acquired BMF syndromes (P=.66). Results of this study are consistent with outcomes of bone marrow transplantation shown by previous series in the same setting and indicate that in pediatric patients with BMF syndrome, CBT from an HLA-identical sibling donor is associated with excellent long-term outcomes and that collection of CB unit at birth of a new sibling is strongly recommended. (C) 2017 American Society for Blood and Marrow Transplantation.
  • Augustine, Erika F.; Adams, Heather R.; de los Reyes, Emily; Drago, Kristen; Frazier, Margie; Guelbert, Norberto; Laine, Minna; Levin, Tanya; Mink, Jonathan W.; Nickel, Miriam; Peifer, Danielle; Schulz, Angela; Simonati, Alessandro; Topcu, Meral; Turunen, Joni A.; Williams, Ruth; Wirrell, Elaine C.; King, Sharon (2021)
    Background: CLN1 disease (neuronal ceroid lipofuscinosis type 1) is a rare, genetic, neurodegenerative lysosomal storage disorder caused by palmitoyl-protein thioesterase 1 (PPT1) enzyme deficiency. Clinical features include developmental delay, psychomotor regression, seizures, ataxia, movement disorders, visual impairment, and early death. In general, the later the age at symptom onset, the more protracted & nbsp;Pediatric Neurology 120 (2021) 38e51 the disease course. We sought to evaluate current evidence and to develop expert practice consensus to support clinicians who have not previously encountered patients with this rare disease. Methods: We searched the literature for guidelines and evidence to support clinical practice recommendations. We surveyed CLN1 disease experts and caregivers regarding their experiences and recommendations, and a meeting of experts was conducted to ascertain points of consensus and clinical practice differences. Results: We found a limited evidence base for treatment and no clinical management guidelines specific to CLN1 disease. Fifteen CLN1 disease experts and 39 caregivers responded to the surveys, and 14 experts met to develop consensus-based recommendations. The resulting management recommendations are uniquely informed by family perspectives, due to the inclusion of caregiver and advocate perspectives. A family-centered approach is supported, and individualized, multidisciplinary care is emphasized in the recommendations. Ascertainment of the specific CLN1 disease phenotype (infantile-, late infantile-, juvenile-, or adult-onset) is of key importance in informing the anticipated clinical course, prognosis, and care needs. Goals and strategies should be periodically reevaluated and adapted to patients' current needs, with a primary aim of optimizing patient and family quality of life. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (
  • Pavlu, Jiri; Labopin, Myriam; Niittyvuopio, Riitta; Socie, Gerard; Yakoub-Agha, Ibrahim; Wu, Depei; Remenyi, Peter; Passweg, Jakob; Beelen, Dietrich W.; Aljurf, Mahmoud; Kroeger, Nicolaus; Labussiere-Wallet, Helene; Peric, Zinaida; Giebel, Sebastian; Nagler, Arnon; Mohty, Mohamad (2019)
    Background: Assessment of measurable residual disease (MRD) is rapidly transforming the therapeutic and prognostic landscape of a wide range of hematological malignancies. Its prognostic value in acute lymphoblastic leukemia (ALL) has been established and MRD measured at the end of induction is increasingly used to guide further therapy. Although MRD detectable immediately before allogeneic hematopoietic cell transplantation (HCT) is known to be associated with poor outcomes, it is unclear if or to what extent this differs with different types of conditioning. Methods: In this retrospective registry study, we explored whether measurable residual disease (MRD) before allogeneic hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia is associated with different outcomes in recipients of myeloablative total body irradiation (TBI)-based versus chemotherapy-based conditioning. We analyzed outcomes of 2780 patients (median age 38 years, range 18-72) who underwent first HCT in complete remission between 2000 and 2017 using sibling or unrelated donors. Results: In 1816 of patients, no disease was detectable, and in 964 patients, MRD was positive. Conditioning was TBI-based in 2122 (76%) transplants. In the whole cohort MRD positivity was a significant independent factor for lower overall survival (OS) and leukemia-free survival (LFS), and for higher relapse incidence (RI), with respective hazard ratios (HR, 95% confidence intervals) of 1.19 (1.02-1.39), 1.26 (1.1-1.44), and 1.51 (1.26-1.8). TBI was associated with a higher OS, LFS, and lower RI with HR of 0.75 (0.62-0.90), 0.70 (0.60-0.82), and 0.60 (0.49-0.74), respectively. No significant interaction was found between MRD status and conditioning. When investigating the impact of MRD separately in the TBI and chemotherapy-based conditioning cohorts by multivariate analysis, we found MRD positivity to be associated with lower OS and LFS and higher RI in the TBI group, and with higher RI in the chemotherapy group. TBI-based conditioning was associated with improved outcomes in both MRD-negative and MRD-positive patients. Conclusions: In this large study, we confirmed that patients who are MRD-negative prior to HCT achieve superior outcomes. This is particularly apparent if TBI conditioning is used. All patients with ALL irrespective of MRD status benefit from TBI-based conditioning in the myeloablative setting.
  • Zárybnický, Tomáš; Heikkinen, Anne; Kangas, Salla M.; Karikoski, Marika; Martinez-Nieto, Guillermo Antonio; Salo, Miia H.; Uusimaa, Johanna; Vuolteenaho, Reetta; Hinttala, Reetta; Sipilä, Petra; Kuure, Satu (2021)
    The modification of genes in animal models has evidently and comprehensively improved our knowledge on proteins and signaling pathways in human physiology and pathology. In this review, we discuss almost 40 monogenic rare diseases that are enriched in the Finnish population and defined as the Finnish disease heritage (FDH). We will highlight how gene-modified mouse models have greatly facilitated the understanding of the pathological manifestations of these diseases and how some of the diseases still lack proper models. We urge the establishment of subsequent international consortiums to cooperatively plan and carry out future human disease modeling strategies. Detailed information on disease mechanisms brings along broader understanding of the molecular pathways they act along both parallel and transverse to the proteins affected in rare diseases, therefore also aiding understanding of common disease pathologies.
  • Baliakas, Panagiotis; Tesi, Bianca; Wartiovaara-Kautto, Ulla; Stray-Pedersen, Asbjørg; Friis, Lone Smidstrup; Dybedal, Ingunn; Hovland, Randi; Jahnukainen, Kirsi; Raaschou-Jensen, Klas; Ljungman, Per; Rustad, Cecilie F.; Lautrup, Charlotte K.; Kilpivaara, Outi; Kittang, Astrid Olsnes; Grønbæk, Kirsten; Cammenga, Jörg; Hellstrom-Lindberg, Eva; Andersen, Mette K. (2019)
    Myeloid neoplasms (MNs) with germline predisposition have recently been recognized as novel entities in the latest World Health Organization (WHO) classification for MNs. Individuals with MNs due to germline predisposition exhibit increased risk for the development of MNs, mainly acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Setting the diagnosis of MN with germline predisposition is of crucial clinical significance since it may tailor therapy, dictate the selection of donor for allogeneic hematopoietic stem cell transplantation (allo-HSCT), determine the conditioning regimen, enable relevant prophylactic measures and early intervention or contribute to avoid unnecessary or even harmful medication. Finally, it allows for genetic counseling and follow-up of at-risk family members. Identification of these patients in the clinical setting is challenging, as there is no consensus due to lack of evidence regarding the criteria defining the patients who should be tested for these conditions. In addition, even in cases with a strong suspicion of a MN with germline predisposition, no standard diagnostic algorithm is available. We present the first version of the Nordic recommendations for diagnostics, surveillance and management including considerations for allo-HSCT for patients and carriers of a germline mutation predisposing to the development of MNs.