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Tjønnfjord, Geir Erland; Osnes, Liv Toril N.; Spetalen, Signe; Haave, Ulla; Popperud, Trine Haug & Maniaol, Angelina H.
[Show all 17 contributors for this article]
(2026).
Anti‐MAG Polyneuropathy: Characterization of the Monoclonal Gammopathy and Clonal B‐Cell Population.
Journal of Immunology Research.
ISSN 2314-8861.
2026(1),
p. 1–9.
doi:
10.1155/jimr/1959235.
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Polyneuropathy due to antibodies to myelin‐associated glycoprotein (MAG) is a rare disease with an estimated prevalence of 1 per 100,000. Symptoms start in the sixth or seventh decade of life, presenting sensory polyneuropathy with sensory ataxia, paresthesia, mild motor deficit, and tremor of upper extremities. The neurophysiological features are compatible with length‐dependent demyelination. It is caused by monoclonal gammopathy of the IgM type produced by clonal B cells. In recent years the monoclonal anti‐CD20 antibody has become the preferred first‐line treatment, but with limited efficacy. We identified a cohort of 42 patients diagnosed with anti‐MAG polyneuropathy. Clinical data were collected retrospectively, and flow cytometry files and immune histochemistry slides were reassessed. We report that in most cases of anti‐MAG polyneuropathy, the monoclonal IgM is kappa‐restricted, the B‐cell population shows lymphoplasmacytic differentiation, MYD88 L265P mutation is a frequent finding, and the clonal B‐cell population includes plasma cells. These findings most likely explain the low efficacy of rituximab monotherapy. We found the burden of symptoms to be high among patients with anti‐MAG polyneuropathy as most of our patients had received intravenous immunoglobulin infusions and/or B‐cell‐directed treatment. We suggest that future treatment protocols for anti‐MAG polyneuropathy should incorporate plasma cell‐directed drugs. Furthermore, we found complement receptor 1 (CD35) to be down regulated on clonal B lymphocytes but not on normal B lymphocytes in these patients. We suggest that this may be a common feature of clonal B lymphocytes in chronic lymphoproliferative diseases.
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Hermansen, Johanne Uthus; Yanping, Yin; Tjønnfjord, Geir Erland; Mato, Anthony R. & Skånland, Sigrid
(2026).
Evolution of the drug sensitivity landscape of chronic lymphocytic leukaemia.
British Journal of Haematology.
ISSN 0007-1048.
doi:
10.1111/bjh.70603.
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Suul, Sara Giæver; Kvam, Ann Kristin; Hestdalen, Malu Lian; Haave, Ulla; Midtvedt, Øyvind & Tjønnfjord, Geir Erland
(2026).
Cryoglobulinemia Type II: Sustained Remission After B-Cell–Directed Therapy.
American Journal of Case Reports.
27.
doi:
10.12659/AJCR.950857.
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Iversen, Per Ole; Gedde-Dahl, Tobias; Tjønnfjord, Geir Erland & Ali, Maryan Mohamed
(2025).
Quality of life the first year after allogeneic haematopoietic stem cell transplantation—A randomized controlled trial examining extracorporeal photophoresis to prevent graft‐versus‐host disease.
British Journal of Haematology.
ISSN 0007-1048.
207(5),
p. 2183–2186.
doi:
10.1111/bjh.70119.
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Skøyeneie, Sigrid Cecilie Tinglum; Fauske, Lena; Wik, Hilde Skuterud; Tjønnfjord, Geir Erland; Gedde-Dahl, Tobias & Myhre, Anders Eivind
(2025).
Patients’ Experiences With Hospital at Home Following Allogenic Hematopoietic Stem Cell Transplantation: A Qualitative Study.
Cancer Nursing.
ISSN 0162-220X.
doi:
10.1097/NCC.0000000000001504.
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Background
Hospital at Home (HaH) models aim to deliver hospital-level care to patients in a home setting. In the context of allogeneic hematopoietic stem cell transplantation (HSCT), HaH is intended to improve patients’ quality of life and reduce symptom burden. However, limited research exists on patients’ perceptions of this innovative care model.
Objective
This study aimed to explore how patients experienced HaH following HSCT.
Methods
A qualitative exploratory research design was employed, utilizing semistructured individual interviews. Sixteen patients who received HaH care following HSCT were interviewed. Reflexive thematic analysis was used to identify themes representing patterns of meaning across the dataset.
Results
The following 3 themes were identified: (1) actively working through the illness experience: participants needed to engage in active coping mechanisms, emphasizing the crucial role of their informal caregivers, (2) recognition of normality in the illness situation: experiencing autonomy and living in a homelike environment enhanced their sense of normality, and (3) fundamental aspects of daily life that promote recovery: psychological and emotional benefits of the private setting, including improved rest, calmness, relaxation, increased physical activity, and the opportunities to engage in familiar daily activities, facilitated recovery in ways that differed from the traditional hospital setting.
Conclusion
This study suggests that HaH positively influences recovery and well-being among HSCT patients and has the potential to improve patient outcomes.
Implications for Practice
HaH offers a viable alternative to traditional hospitalization, promoting a more personalized approach to care.
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Busterud, Kari; Remberger, Mats; Bentsen, Pål Tore; Jerm, Marianne Brenn; Gedde-Dahl, Tobias & Kittang, Astrid Marta Olsnes
[Show all 7 contributors for this article]
(2025).
Allogeneic stem cell transplantation for acute myeloid leukaemia 2005–22.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
145(12).
doi:
10.4045/tidsskr.25.0001.
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Bakgrunn: Allogen stamcelletransplantasjon er den eneste kurative behandlingen ved en rekke blod- og benmargssykdommer. Formålet med denne undersøkelsen er å beskrive hvordan allogen stamcelletransplantasjon ved akutt myelogen leukemi benyttes i Norge og undersøke eventuelle ulikheter mellom de fire helseregionene.
Materiale og metode: I perioden 1.1.2005 til 31.12.2022 ble 2 979 personer diagnostisert med akutt myelogen leukemi i Norge. Vi identifiserte alder, remisjonsstatus, donorkarakteristika, overlevelse og transplantasjonsrelatert dødelighet hos pasientene som ble behandlet med allogen stamcelletransplantasjon.
Resultater: I studieperioden gjennomgikk 674/2 979 (22,6 %) av personene med påvist akutt myelogen leukemi allogen stamcelletransplantasjon. Det var et økende antall behandlinger over tid: fra 14 transplantasjoner i 2005 til 67 i 2020. Behandlingsresultatene ble progressivt bedre: femårs overlevelse økte fra 48 % i perioden 2005–10, til 63 % i perioden 2017–22. Median alder hos pasientene fra Helse Midt (48 år) og Helse Vest (50 år) var lavere enn hos pasientene fra Helse Sør-Øst (54 år) og Helse Nord (60 år). Det var ingen forskjeller mellom helseregionene når det gjaldt kjønn, remisjonsstatus og bruk av familiedonor og ubeslektet donor.
Fortolkning: Allogen stamcelletransplantasjon er i dag en sentral del av behandlingen ved akutt myelogen leukemi. Stadig flere pasienter behandles med allogen stamcelletransplantasjon uten at behandlingsresultatene forringes.
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Gudmundstuen, Anne Marte; Iversen, Per Ole; Pesonen, Maiju; Hjermstad, Marianne Jensen; Bye, Asta & Tjønnfjord, Geir Erland
[Show all 7 contributors for this article]
(2025).
Comparing indirect calorimetry and predictive equations for energy expenditure - 1 year follow-up of adult hematopoietic stem cell transplanted recipients.
Clinical Nutrition ESPEN.
ISSN 2405-4577.
70,
p. 218–226.
doi:
10.1016/j.clnesp.2025.09.027.
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Background and aims
Recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) often undergo body composition changes that may impact their energy expenditure (EE), however, the accurate energy requirements may be difficult to estimate. Indirect calorimetry (IC) is recommended as the gold standard to assess measured energy expenditure (mEE), but its use is resource-demanding and thus rarely applied compared to predictive energy equations. Here we evaluated the agreement between mEE by IC and EE estimated by several predictive energy equations, or the ESPEN recommendation, during 1-year follow-up of adult allo-HSCT recipients.
Methods
We examined 117 adult patients with hematological malignancies who received allo-HSCT. mEE was assessed by IC in non-fasting patients before transplantation, and at 3, 6, 9 and 12 months post-allo-HSCT. Agreement between mEE and predictive values using the Harris-Benedict-HB, Mifflin St. Jeor-MSJ, Ireton Jones-IJ equations and the fixed ESPEN recommendation of 25 kcal/kg/day was evaluated using Bland–Altman analysis and accuracy within ± 10 %. Changes in mEE over time were analyzed using linear mixed model with age as a covariate.
Results
A total of 509 mEE measurements by IC were obtained. HB and MSJ overestimated mEE on average (mean bias: + 2.9 and + 3.8 kcal/kg/day), while IJ, and the fixed ESPEN recommendation underestimated mEE (biases: – 0.7 and – 4.7 kcal/kg/day, respectively). None of the equations or the fixed ESPEN recommendation achieved > 50 % accuracy within ± 10 % of mEE by IC. IJ had the highest variability and widest limits of agreement. mEE changed significantly over time (p < 0.001), with no significant differences between the initially randomized intervention and control group (p = 0.982). Mean mREE was 24.74 ± 3.80 kcal/kg/day and 31.14 ± 4.91 kcal/kg/day when adjusted for FFM. Age was not significantly associated with mREE (p = 0.198).
Conclusion
Our findings indicate that commonly used predictive equations and the fixed ESPEN recommendation showed limited accuracy compared with mEE in allo-HSCT recipients. Only mEE obtained by IC captured longitudinal changes in EE during the first year post-transplantation. mEE by IC varied significantly the first year post-transplant. ClinicalTrials.gov, ID NCT01181076.
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Hermansen, Johanne Uthus; Athanasiadis, Paschalis; Yanping, Yin; Rise, Anne-sofie Forfot; Arribas, Alberto J. & Cascione, Luciano
[Show all 13 contributors for this article]
(2025).
Proteasome inhibition overcomes resistance to targeted therapies in B-cell malignancy models and in an index patient.
Cell Death & Disease.
16(1),
p. 1–14.
doi:
10.1038/s41419-025-07884-7.
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Treatment of B-cell malignancies with the PI3K inhibitor (PI3Ki) idelalisib often results in high toxicity and resistance, with limited treatment alternatives for relapsed/refractory patients since idelalisib is recommended as a later or last line therapy. To investigate resistance mechanisms and identify alternative treatments, we studied functional phenotypes of idelalisib-resistant B-cell malignancy models. The idelalisib-resistant KARPAS1718 model remained sensitive to Bcl-2 inhibitors (Bcl-2i), whereas the resistant VL51 model showed reduced sensitivity compared to parental cells. Sensitivity correlated with phosphorylation and expression of the Bcl-2 family members Bcl-2 and Bim. Target addiction scoring revealed high dependence on the proteasome, and proteasome inhibitors (PI) were effective across models and in primary chronic lymphocytic leukemia (CLL) cells, independently of their PI3Ki- or Bcl-2i-sensitivities. PI treatment consistently upregulated Bim and Mcl-1, while Bcl-2 increased in KARPAS1718 and CLL cells. Bcl-2i plus PI combinations led to an additive effect in these models. A multi-refractory CLL patient in the IMPRESS-Norway trial (NCT04817956) treated with Bcl-2i plus PI showed initial clinical improvement but relapsed within four months. Treatment induced Bim and Mcl-1 upregulation and reduced cytotoxic CD8 + T-cell and CD56 dim NK-cell populations. Our findings suggest that PIs may overcome resistance to targeted therapies, and warrant further studies to optimize clinical responses.
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Skaarud, Kristin Aneta Joan; Gudmundstuen, Anne Marte; Pesonen, Maiju; Hjermstad, Marianne Jensen; Iversen, Per Ole & Tjønnfjord, Geir Erland
(2025).
The role of fat-soluble vitamins for graft-versus host disease after myeloablative conditioning in allogeneic stem cell transplanted patients.
Scientific Reports.
15.
doi:
10.1038/s41598-024-84805-2.
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Whether the fat-soluble vitamins A, D, E, and K are associated with development of graft-versus-host disease (GvHD) after allogeneic stem cell transplantation, is unclear. We assessed if the levels of these vitamins were associated with development of GvHD during the first year after transplantation using data from a two-armed randomized nutritional intervention trial. Changes in plasma levels during 1-year follow-up were analyzed using a linear mixed model for repeated measurements. Vitamin A, D, E, and K levels changed significantly the first year in both study arms (p < 0.001). Higher levels of vitamin E over time were associated with less acute GvHD grades 3–4 (OR = 0.997, 95% CI: (0.994, 0.999), p = 0.017). No associations were found with vitamin A, D, E and K levels and chronic GvHD. Multivariable analysis adjusted for treatment group, age, pre-transplant vitamin level and risk factors for GvHD did not change the results. Six weeks post-transplantation, higher levels of vitamin E were associated with less acute GvHD grades 3–4, (p = 0.012). In conclusion, we found an association between higher levels of vitamin E over time and less severe acute GvHD. Whether this reflects a causal relationship warrants further study. ClinicalTrials.gov (NCT01181076).
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Brunetti, Marta; Andersen, Kristin; Spetalen, Signe; Tjønnfjord, Geir Erland; Heim, Sverre & Micci, Francesca
(2025).
Cryptic Rearrangement of the KMT2A Gene in a B‐cell Acute Lymphoblastic Leukemia.
Anticancer Research.
ISSN 0250-7005.
45(3),
p. 921–928.
doi:
10.21873/anticanres.17479.
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Background/Aim: A 30-year-old female diagnosed with B cell acute lymphoblastic leukemia (B-ALL) had a normal karyotype at diagnosis.
Case Report: The case was investigated further by fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH), and reverse-transcription polymerase chain reaction (RT-PCR) followed by Cycle sequencing. The diagnostic karyotype was normal (46,XX), but FISH studies on tumor cells using a KMT2A break-apart probes showed that the proximal part of KMT2A was inserted into an apparently normal chromosome 4 with concomitant loss of the distal part of the probe. aCGH identified losses within 11q23.3 and 4q21.3q22.1 with the breakpoints mapping inside the KMT2A and AFF1 loci. The presence of the putative KMT2A::AFF1 fusion gene was confirmed by FISH analysis and RT-PCR/Cycle sequencing; an in-frame fusion was detected between KMT2A (exon 9) and AFF1 (exon 6). The patient underwent allogenic stem cell transplantation and reached complete remission.
Conclusion: This case highlights the need to supplement banding cytogenetics with appropriate molecular (cyto)genetic techniques whenever the karyotype does not reveal characteristic aberrations. Although KMT2A rearrangements in both lymphoblastic and myeloid acute leukemias usually arise through karyotypically visible chromosomal recombinations, this is not always the case.
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Mishra, Vinod Kumar; Gedde-Dahl, Tobias; Remberger, Mats; Solvang, Grethe; Selvaag, Kristin Mill Lien & Fosseng, Arne
[Show all 10 contributors for this article]
(2025).
Hospital at Home Following Allogeneic Hematopoietic Stem Cell Transplantation: An Economic Analysis.
Healthcare.
doi:
10.3390/healthcare13141648.
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Background: Advanced home care is becoming increasingly common for cancer patients and serves as a viable alternative to inpatient hospital care. The transition to home care is driven by both the rising costs of healthcare and evidence indicating better quality of care. This study aims to compare the costs of hospital-at-home treatment and in-hospital care for patients undergoing allo-HSCT. Methods: The cost analysis was conducted as a case–control study comparing the costs of allo-HSCT at home (HaH) to the costs of allo-HSCT for patients receiving in-hospital care (INH). The cost evaluation was conducted from the hospital’s perspective, which means that costs incurred outside the hospital setting were not included. Post-procedural costs for the first year after allo-HSCT included all readmissions and outpatient visits at Oslo University Hospital. Results: The cost for the peritransplant period could be reduced by up to 33% by treating allo-HSCT recipients at home instead of in the hospital. During the study period, 24% of the allo-HSCT recipients were treated at home, but our data from 2021 and 2022 indicate that at least a third of the patients scheduled for allo-HSCT are candidates for HaH. Conclusions: The findings demonstrate that patients in advanced home care experience significantly lower total costs compared to those receiving in-hospital treatment.
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Skøyeneie, Sigrid Cecilie Tinglum; Wik, Hilde Skuterud; Tjønnfjord, Geir Erland; Fauske, Lena; Gedde-Dahl, Tobias & Myhre, Anders Eivind
(2025).
Family Caregivers’ Experiences of Hospital at Home Following Allogeneic Haematopoietic Stem Cell Transplantation: A Qualitative Study.
European Journal of Cancer Care.
ISSN 0961-5423.
2025(1).
doi:
10.1155/ecc/7043910.
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Purpose: The use of Hospital at Home (HaH) is expanding globally, including in the context of allogeneic haematopoietic stem cell transplantation (HSCT), as an innovative care model that delivers hospital-equivalent care to patients in a home setting. The HaH model designed for HSCT relies on informal caregivers, such as next of kin or friends. Given the limited research on caregivers’ perceptions of HaH, this study aimed to explore how informal caregivers of patients undergoing HSCT experienced HaH.
Method: Using a phenomenological interpretive approach, semistructured individual interviews were conducted with 14 family caregivers. Data were analysed using reflexive thematic analysis.
Results: The analysis identified three themes: (1) On the inside as a caregiver, (2) Variation in caregiver burden and (3) Appreciating normality. Caregivers valued the opportunity to be physically present and involved in caring for the patient during HSCT. Although most had to undertake an active caregiving role, they reported varying levels of involvement and distress. Caregivers also highlighted the sensation of normality that HaH fostered, emphasising that maintaining a familiar routine in the home setting was less exhausting than traditional hospital care.
Conclusion: This study found that family caregivers appreciated being physically present in HaH, experiencing a sensation of being ‘on the inside’ and closely sharing the patient’s treatment journey, in contrast to during hospitalisation. The findings revealed diverse experiences of caregiving and associated distress, underscoring the importance of adequately preparing caregivers for their role and ensuring appropriate support.
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Podgorica, Mirjam; Drivet, Elsa Maria Caroline; Viken, Jonas Krag; Richman, Alyssa; Vestbøstad, Johanne Bonsaksen & Szodoray, Peter
[Show all 12 contributors for this article]
(2024).
Transcriptome analysis of primary adult B-cell lineage acute lymphoblastic leukemia identifies pathogenic variants and gene fusions, and predicts subtypes for in depth molecular diagnosis.
European Journal of Haematology.
ISSN 0902-4441.
112(5),
p. 731–742.
doi:
10.1111/ejh.14164.
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Background B-cell acute lymphoblastic leukemia (B-ALL) is classified into subgroups based on known driver oncogenes and molecular lesions, including translocations and recurrent mutations. However, the current diagnostic tests do not identify subtypes or oncogenic lesions for all B-ALL samples, creating a heterogeneous B-ALL group of unknown subtypes. Methods We sorted primary adult B-ALL cells and performed transcriptome analysis by bulk RNA sequencing (RNA-seq). Results Transcriptomic analysis of an adult B-ALL cohort allowed the classification of four patient samples with subtypes that were not previously revealed by standard gene panels. The leukemia of two patients were of the DUX4 subtype and two were CRLF2+ Ph-like B-ALL. Furthermore, single nucleotide variant analysis detected the oncogenic NRAS-G12D, KRAS-G12D, and KRAS-G13D mutations in three of the patient samples, presenting targetable mutations. Additional oncogenic variants and gene fusions were uncovered, as well as multiple variants in the PDE4DIP gene across five of the patient samples. Conclusion We demonstrate that RNA-seq is an effective tool for precision medicine in B-ALL by providing comprehensive molecular profiling of leukemia cells, identifying subtype and oncogenic lesions, and stratifying patients for appropriate therapy.
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Imbery, John Franklin; Wiik, Celina Marie; Heinzelbecker, Julia; Jebsen, Jenny Karoline; Dobbing, Mia K. & Bottini, Nunzio
[Show all 12 contributors for this article]
(2024).
CD38 regulates chronic lymphocytic leukemia proliferation via CD45 phosphatase activity.
Molecular Therapy: Oncology.
32(3),
p. 1–15.
doi:
10.1016/j.omton.2024.200841.
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Chronic lymphocytic leukemia (CLL) growth is dependent on both B cell receptor (BCR) signaling and signals from microenvironmental T helper (Th) cells. We previously described a mechanism where Th cells enhance BCR signaling and proliferation through CD45 phosphatase activity regulation via galectin-1 and CD43. The CLL negative prognostic indicator CD38 is linked to BCR signaling and proliferation, with its expression induced by Th cells. Here, we explore a link between CD38 and CD45 phosphatase activity regulation using patient-derived material in a Th-CLL cell co-culture model. Results demonstrate CD43 and galectin-1 are co-expressed with CD38, defining proliferative CLL cells with augmented CD45 activity. CD38 enzymatic and receptor inhibition regulated CD43 and galectin-1 expression, CD45 activityhi populations, and CLL proliferation, while leaving Th cells largely unaffected. Mechanistically, CD38- or LGALS1 (galectin-1)-deficient malignant B cell lines further confirmed CD38-mediated regulation of CD45 activity and BCR signaling through CD43 expression and galectin-1 surface binding, while galectin-1 contributed to CD43/CD45 colocalization. Together, this highlights CD38 as an important regulator of CD45 activity via CD43 and galectin-1, in turn acting as a positive modulator of CLL proliferation. Ultimately, the CD38/CD45 molecular hub could be an important therapeutic target in CLL.
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Fageräng, Beatrice Linnea Christina; Cyranka, Leon; Schjalm, Camilla; Ekholt, Karin; Larsen, Carina Sandem & Heinzelbecker, Julia
[Show all 14 contributors for this article]
(2024).
The function of the complement system remains fully intact throughout the course of allogeneic stem cell transplantation.
Frontiers in Immunology.
15.
doi:
10.3389/fimmu.2024.1422370.
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Introduction: Hematopoietic stem cell transplantation (HSCT) is associated with immune complications and endothelial dysfunction due to intricate donor-recipient interactions, conditioning regimens, and inflammatory responses. Methods: This study investigated the role of the complement system during HSCT and its interaction with the cytokine network. Seventeen acute myeloid leukemia patients undergoing HSCT were monitored, including blood sampling from the start of the conditioning regimen until four weeks post-transplant. Clinical follow-up was 200 days. Results: Total complement functional activity was measured by WIELISA and the degree of complement activation by ELISA measurement of sC5b-9. Cytokine release was measured using a 27-multiplex immuno-assay. At all time-points during HSCT complement functional activity remained comparable to healthy controls. Complement activation was continuously stable except for two patients demonstrating increased activation, consistent with severe endotheliopathy and infections. In vitro experiments with post-HSCT whole blood challenged with Escherichia coli, revealed a hyperinflammatory cytokine response with increased TNF, IL-1β, IL-6 and IL-8 formation. Complement C3 inhibition markedly reduced the cytokine response induced by Staphylococcus aureus, Aspergillus fumigatus, and cholesterol crystals. Discussion: In conclusion, HSCT patients generally retained a fully functional complement system, whereas activation occurred in patients with severe complications. The complement-cytokine interaction indicates the potential for new complement-targeting therapeutic strategies in HSCT.
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Hamnvik, Lars Henrik; Tjønnfjord, Geir Erland; Spetalen, Signe & Dalgaard, Jakob
(2024).
Long-lasting severe anemia following treatment with natalizumab for relapsing–remitting multiple sclerosis: a case report.
Journal of Medical Case Reports.
18(1).
doi:
10.1186/s13256-024-04562-8.
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Background Natalizumab is a monoclonal antibody used to treat patients with relapsing–remitting multiple sclerosis. Anemia is a recognized side effect, but it is usually mild and of a short duration when natalizumab is stopped. Here, we describe a case of a young woman with severe and especially long lasting anemia associated with treatment with natalizumab, persisting up to a year after treatment was stopped. Case presentation A 24 year-old Caucasian woman with relapsing–remitting multiple sclerosis developed severe transfusion dependent anemia after 27 infusions with natalizumab, which was her first and only treatment for her multiple sclerosis. Extensive hematologic diagnostics did not reveal any malignant cause or any other plausible non-malignant cause for her anemia. The bone marrow was found to be hypercellular, with a maturation arrest of the erythropoiesis and with grade 1–2 fibrosis. No specific treatment for the anemia was given. The hemoglobin level showed signs of spontaneous increase after nearly one year after natalizumab was discontinued. Conclusion Severe anemia can be caused by treatment with natalizumab. This case adds information to the few other similar reported cases, demonstrating the potential duration of the anemia, as well as detailed description of hematologic findings. The mechanism is most likely due to inhibition of α4 subunit of the α4β1-integrin, which is present on both lymphocytes and erythroid precursor cells.
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Grønvold, Bjørn Christer Linder; Ali, Maryan Mohamed; Myklebust, Tor Åge; Lenartova, Andrea; Remberger, Mats & Abrahamsen, Ingerid Weum
[Show all 10 contributors for this article]
(2024).
Allogeneic stem cell transplant recipients surviving at least 2 years without relapse: outcome and risk factors.
eJHaem.
5(1),
p. 117–124.
doi:
10.1002/jha2.842.
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Outcomes of 2-year survivours undergoing allo-haematopoietic stem cell transplantation at Oslo University Hospital were retrospectively assessed with the objectives of identification of risk factors for late death as possible means for precautionary measures and interventions to improve long-term survival.
421 patients with haematological malignancy, transplanted between 2005 and 2019, alive and free of disease after 2 years were included with data reported from The OUS-HSCT registry. Median follow-up was 6.2 years (2.016.1), and 232 patients (55%) were observed for minimum 5 years.
The probability of being alive 5 and 10 years after HSCT was 86% and 76%. Primary risk factors for late death included initial diagnosis of age ≥ 60 years, chronic lymphocytic leukaemia (CLL), previous blood stream- or invasive fungal infection (BSI, IFI), and chronic graft-versus-host disease (cGVHD). Transplant-related mortality (TRM) and relapse at 5 years were 9.0% and 7.7%, respectively. Two factors were associated with the latter: cytomegalovirus (CMV) seronegative donor and CLL. Compared with the age- and gender-matched Norwegian general population, life expectancy was lower for each disease, except for CML.
The prospect for the long-term survival is good for 2-year survivors of the allogeneic hematopoietic stem cell transplantation. However, life expectancy remains inferior to the age- and gender-matched general population. Optimising prophylaxis and treatment for chronic GVHD, BSI and IFI are needed along with the improved adherence to guidelines for early detection of secondary malignancies. Measures to improve immune reconstitution, possibly the microbiota, and the use of CMV seropositive donors regardless of recipient sero-status may be warranted and should be addressed in further studies.
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Qvigstad, Christian; Sørensen, Lars A Q; Tjønnfjord, Geir Erland; Holme, Pål Andre; Pabinger, Ingrid & Hermans, Cedric
[Show all 27 contributors for this article]
(2024).
The association between unemployment and treatment among adults with hemophilia.
Research and Practice in Thrombosis and Haemostasis (RPTH).
8(5).
doi:
10.1016/j.rpth.2024.102514.
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Background People with hemophilia often experience pain and suffer from comorbidities related to their bleeding disorder. Consequently, unemployment due to disability is prevalent among people with hemophilia. Objectives To explore associations between unemployment due to disability and treatment while adjusting for known risk factors for unemployment. Methods Collecting data from 20 hemophilia centers from 15 European countries, the Age-related DeVelopments ANd ComorbiditiEs (ADVANCE) in hemophilia study recruited 785 participants aged 40 years and over with hemophilia A or B. A comprehensive electronic case report form included items related to patient characteristics, demographic information, past and current treatment regimens, and medical history, including a lifelong history of comorbidities. Baseline data from the ADVANCE study was analyzed using descriptive statistics and logistic regression models. Results Employment status was available for 756 of 785 participants aged 40 to 88 years (median, 53 years). We used regression analysis to compare people with hemophilia who were fully employed with those who were unemployed due to disability. This analysis included 424 participants. Using multivariable logistic regression, we found that age (odds ratio [OR], 1.07; P < .01), severe hemophilia (OR, 10.81; P < .01), current smoker (OR, 2.53; P < .01), and psychiatric disorder (OR, 4.18; P = .02) were associated with increased odds of unemployment due to disability. In contrast, prophylactic treatment (OR, 0.44; P = .01) was associated with decreased odds. Conclusion Our analysis suggests that by maintaining factor levels above a critical threshold (3%-5%), prophylactic treatment for people with hemophilia could help avoid unemployment due to disability. While prophylaxis is more costly and can be burdensome, the benefits to material well-being and quality of life could be substantial.
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Måseide, Ragnhild Johanne; Berntorp, Erik; Astermark, Jan; Olsson, Anna; Bruzelius, Maria & Frisk, Tony
[Show all 11 contributors for this article]
(2024).
Nonneutralizing antibodies in Nordic persons with moderate hemophilia A and B (the MoHem study).
Research and Practice in Thrombosis and Haemostasis (RPTH).
8(8).
doi:
10.1016/j.rpth.2024.102611.
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Background The impact of nonneutralizing antibodies (NNAs) in moderate hemophilia is elusive. Objectives To explore the presence of NNAs in Nordic persons with moderate hemophilia A (MHA) and B (MHB) in relation to treatment modality, clinical outcome, history of inhibitor, and the corresponding factor VIII (FVIII)/factor IX (FIX) gene mutation. Methods A cross-sectional multicenter study covering persons with MHA and MHB in Sweden, Finland, and Norway. Inhibitors were analyzed with the Bethesda assay, and NNAs were detected by enzyme-linked immunosorbent assay. Results Plasma samples from 137 MoHem study participants (median age 29 years; Q1-Q3, 15-54) were analyzed. NNAs were present in 11 of 82 (13%) of people with MHA and 7 of 55 (13%) of those with MHB irrespective of prophylactic or on-demand treatment, most frequently after 150 exposure days (EDs). Three NNA positive patients had a history of high-titer inhibitor, but current analyses were negative (<0.6 BU/mL). Baseline FVIII/FIX activity was similar among NNA positive and negative patients. Current bleeding rates were low, but patients with NNAs captured a higher Hemophilia Joint Health Score (7 [median]; Q1-Q3, 3-20 vs. 4; 1-9) (P = .02) and had more frequently undergone arthroplasty or arthrodesis (5 [33%] vs. 15 [13%]) (P = .03). Conclusion NNAs were detected in 13% of Nordic persons with MHA and MHB, most frequently after 150 EDs. Patients with NNAs had more severe hemophilic arthropathy than patients without NNAs. The relationship between NNAs and clinical outcome in hemophilia should be further explored in a large cohort including pharmacokinetics and longitudinal observations with repeated blood sampling.
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Berentsen, Sigbjørn; Vos, Josephine M.I.; Malecka, Agnieszka Maria; Tjønnfjord, Geir Erland & D’Sa, Shirley
(2024).
The impact of individual clinical features in cold agglutinin disease: hemolytic versus non-hemolytic symptoms.
Expert Review of Hematology.
ISSN 1747-4086.
doi:
10.1080/17474086.2024.2372333.
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Iversen, Per Ole; Guéant, Jean-Louis; Oussalah, A; Refsum, Helga; Nexo, Ebba & Tjønnfjord, Geir Erland
[Show all 7 contributors for this article]
(2024).
Heterozygous Mutations in Both the AMN and CBS Genes: Double Haploinsufficiency as an Unusual Cause of Vitamin B12 Deficiency-A Case Report.
Clinical Case Reports.
12(11).
doi:
10.1002/ccr3.9600.
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Vitamin B12 deficiency is usually simple to diagnose. However, our patient demonstrates that in difficult cases, the ordinary clinician may need a transdisciplinary approach. The finding of a double haploinsufficiency as a possible cause of vitamin B12 deficiency in our patient, illustrates the usefulness of performing large panel clinical exome sequencing.
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Malecka, Agnieszka Maria; Østlie, Ingunn; Trøen, Gunhild; Malecki, Jedrzej Mieczyslaw; Delabie, Jan & Tierens, Anne
[Show all 9 contributors for this article]
(2023).
Gene expression analysis revealed downregulation of complement receptor 1 in clonal B cells in cold agglutinin disease.
Clinical and Experimental Immunology.
ISSN 0009-9104.
216(1),
p. 45–54.
doi:
10.1093/cei/uxad135.
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Abstract Cold agglutinin disease (CAD) is a rare B-cell lymphoproliferative disorder of the bone marrow, manifested by autoimmune hemolytic anemia caused by binding of monoclonal IgM autoantibodies to the I antigen. Underlying genetic changes have previously been reported, but their impact on gene expression profile has been unknown. Here, we define differentially expressed genes in CAD B cells. To unravel downstream alteration in cellular pathways, gene expression by RNA sequencing was undertaken. Clonal B-cell samples from 12 CAD patients and IgM-expressing memory B cells from 4 healthy individuals were analyzed. Differential expression analysis and filtering resulted in 93 genes with significant differential expression. Top upregulated genes included SLC4A1, SPTA1, YBX3, TESC, HBD, AHSP, TRAF1, HBA2, RHAG, CA1, SPTB, IL10, UBASH3B, ALAS2, HBA1, CRYM, RGCC, KANK2, and IGHV4-34. They were upregulated at least 8-fold, while complement receptor 1 (CR1/CD35) was downregulated 11-fold in clonal CAD B cells compared to control B cells. Flow cytometry analyses further confirmed reduced CR1 (CD35) protein expression by clonal CAD IgM+ B cells compared to IgM+ memory B cells in controls. CR1 (CD35) is an important negative regulator of B-cell activation and differentiation. Therefore, reduced CR1 (CD35) expression may increase activation, proliferation, and antibody production in CAD-associated clonal B cells.
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Vo, Camilla Dao; Myhre, Anders Eivind; Abrahamsen, Ingerid Weum; Remberger, Mats; Mattsson, Jonas & Fløisand, Yngvar
[Show all 10 contributors for this article]
(2023).
Allogen stamcelletransplantasjon hos voksne 2015–21.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
143(4).
doi:
10.4045/tidsskr.22.0521.
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BAKGRUNN Allogen stamcelletransplantasjon er eneste kurative behandling for flere maligne og ikke-maligne blodsykdommer, og er assosiert med risiko for alvorlige komplikasjoner. De siste årene er det innført flere endringer med mål om å redusere behandlingsrelaterte komplikasjoner. Denne retrospektive studien gjennomgår kvalitetsindikatorer for pasienter som gjennomgikk transplantasjon i perioden 2015–21. MATERIALE OG METODE Studien inkluderte 589 voksne pasienter som ble behandlet med allogen stamcelletransplantasjon for første gang ved Oslo universitetssykehus fra mai 2015 til mai 2021. Tre toårsperioder er sammenliknet med deskriptive metoder. RESULTATER Fra 2015 til 2021 økte antall årlige førstegangstransplantasjoner fra 85 til 113. Ettårsoverlevelse økte fra 68 % i første toårsperiode til 74 % i andre periode og til 82 % i siste periode. Det var en reduksjon i både akutt og kronisk transplantat-mot-vert-sykdom, og andelen pasienter i live ett år etter transplantasjonen uten transplantat-mot-vert-sykdom eller residiv økte fra 42 % til 60 % i studieperioden. FORTOLKNING Siden 2015 er antall transplantasjoner økt samtidig som overlevelsen er forbedret og risikoen for komplikasjoner lavere.
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Gudmundstuen, Anne Marte; Efficace, Fabio; Tjønnfjord, Geir Erland; Skaarud, Kristin Aneta Joan; Cottone, Francesco & Hjermstad, Marianne Jensen
[Show all 7 contributors for this article]
(2023).
The prognostic value of patient-reported outcomes in allogeneic hematopoietic stem cell transplantation: exploratory analysis of a randomized nutrition intervention trial.
Annals of Hematology.
ISSN 0939-5555.
102(4),
p. 927–935.
doi:
10.1007/s00277-023-05149-x.
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Whether patient-reported outcomes (PROs) can predict overall survival (OS) and non-relapse mortality (NRM) among recipients of allogeneic stem cell transplantation (allo-HSCT), is unclear. We performed an exploratory analysis of the prognostic value of patient-reported outcomes (PROs) among 117 recipients of allogeneic stem cell transplantation (allo-HSCT) who participated in a randomized nutrition intervention trial. Cox proportional hazards models were used to investigate possible associations between PROs collected pre-allo-HSCT (baseline) using scores from the EORTC Quality of Life Questionnaire-Core 30 (QLQ-C30) and 1-year overall survival (OS), whereas logistic regression was used to study associations between these PROs and 1-year non-relapse mortality (NRM). Multivariable analyses indicated that only the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) and the European Bone Marrow Transplantation (EBMT) risk score were associated with 1-year OS. In the multivariable model including clinical-sociodemographic factors for 1-year NRM, our analysis showed that living alone (p=0.009), HCT-CI (p=0.016), EBMT risk score (p=0.002), and stem cell source (p=0.046) could be associated with 1-year NRM. Moreover, in the multivariable model, our analysis showed that only appetite loss from the QLQ-C30 was associated with 1-year NRM (p=0.026). In conclusion, in this specific setting, our analysis suggests that the commonly used HCT-CI and EBMT risk scores could be predictive for both 1-year OS and 1-year NRM, whereas baseline PROs in general were not.
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Ali, Maryan Mohamed; Gedde-Dahl, Tobias; Osnes, Liv T. N.; Perrier, Flavie; Veierød, Marit Bragelien & Tjønnfjord, Geir Erland
[Show all 7 contributors for this article]
(2023).
Extracorporeal Photopheresis as Graft-versus-Host Disease Prophylaxis: A Randomized Controlled Trial.
Transplantation and Cellular Therapy (TCT).
ISSN 2666-6375.
29(6),
p. 364.e1–364.e11.
doi:
10.1016/j.jtct.2023.02.023.
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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the sole curative option for many patients diagnosed with hematologic malignancies. A major obstacle is graft-versus-host disease (GVHD), causing significant morbidity and mortality. Extracorporeal photopheresis (ECP) is an increasingly applied treatment for GVHD, owing in part to its favorable safety profile. In contrast, reports on the use of ECP to prevent GVHD are rare, and randomized controlled trials (RCTs) are lacking. We conducted an RCT to assess whether ECP applied post-transplantation could prevent the development of GVHD within the first year of transplantation. We enrolled 157 patients (age 18 to 74 years) with a hematologic malignancy undergoing their first allo-HSCT, randomized as 76 to the intervention group and 81 to the control group. ECP was initiated directly on engraftment and was planned twice weekly for 2 weeks, then once weekly for 4 weeks. GVHD, relapse, and death were analyzed by Cox regression analysis. During the first year, 45 patients in the intervention group and 52 control patients developed GVHD (hazard ratio [HR], .82; 95% confidence interval [CI], .55 to 1.22; P = .32). There were no differences in acute or chronic GVHD or its organ distribution in this intention-to-treat RCT. A per-protocol analysis revealed a significant difference in GVHD between the intervention group (per-protocol; n = 39 of 76) and the control group (n = 77), 46% versus 68%, respectively (HR, .47; 95% CI, .27 to .80; P = .006). Relapse occurred in 15 patients in the intervention group and in 11 control patients (HR, 1.38; 95% CI, .64 to 3.01; P = .42). GVHD-free relapse-free survival, event-free survival, overall survival, and nonrelapse mortality did not differ significantly between the 2 study groups. There also was no significant difference in immune reconstitution between the 2 groups. This first intention-to-treat RCT investigating ECP as GVHD prophylaxis in allo-HSCT for hematologic malignancy does not support the use of ECP as an adjunct to standard drug-based GVHD prophylaxis.
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Hermansen, Johanne Uthus; Yin, Yanping; Urban, Aleksandra; Myklebust, Camilla Victoria; Karlsen, Linda & Melvold, Katrine
[Show all 11 contributors for this article]
(2023).
A tumor microenvironment model of chronic lymphocytic leukemia enables drug sensitivity testing to guide precision medicine.
Cell death discovery.
9.
doi:
10.1038/s41420-023-01426-w.
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Abstract The microenvironment of chronic lymphocytic leukemia (CLL) cells in lymph nodes, spleen, and bone marrow provides survival, proliferation, and drug resistance signals. Therapies need to be effective in these compartments, and pre-clinical models of CLL that are used to test drug sensitivity must mimic the tumor microenvironment to reflect clinical responses. Ex vivo models have been developed that capture individual or multiple aspects of the CLL microenvironment, but they are not necessarily compatible with high-throughput drug screens. Here, we report on a model that has reasonable associated costs, can be handled in a regularly equipped cell lab, and is compatible with ex vivo functional assays including drug sensitivity screens. The CLL cells are cultured with fibroblasts that express the ligands APRIL, BAFF and CD40L for 24 h. The transient co-culture was shown to support survival of primary CLL cells for at least 13 days, and mimic in vivo drug resistance signals. Ex vivo sensitivity and resistance to the Bcl-2 antagonist venetoclax correlated with in vivo responses. The assay was used to identify treatment vulnerabilities and guide precision medicine for a patient with relapsed CLL. Taken together, the presented CLL microenvironment model enables clinical implementation of functional precision medicine in CLL.
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Hillarp, Andreas; Holme, Pål Andre; Wåland, Erik Pareli; Skogstad, Marie Jeanette; Henriksson, Carola Elisabeth & Tjønnfjord, Geir Erland
[Show all 7 contributors for this article]
(2023).
Report on 4 cases with decreased recovery due to neutralizing antibodies specific for PEGylated recombinant factor VIII.
Journal of Thrombosis and Haemostasis.
ISSN 1538-7933.
21(10),
p. 2771–2775.
doi:
10.1016/j.jtha.2023.07.019.
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Background The immunogenicity, safety, and efficacy of recombinant factor VIII (rFVIII) have gained increasing interest after the introduction of extended half-life products with various modifications of the rFVIII molecule, such as covalent attachment of polyethylene glycol (PEG). Anti-PEG antibodies may be associated with a temporary reduction of FVIII recovery, but according to previous studies, they usually disappear after continuous dosing. Anti-PEG antibodies with an inhibitory capacity have never been demonstrated in patients treated with PEGylated rFVIII products. Objectives To routinely switch from standard half-life to PEGylated extended half-life rFVIII products in patients with hemophilia A. Methods From December 2022 until May 2023, 83 adults with hemophilia A attending Oslo Haemophilia Comprehensive Care Centre received a test dose with a PEGylated rFVIII product to switch treatment. Four patients presented with decreased recovery without the presence of an FVIII inhibitor. Accordingly, we performed a variant inhibitor test utilizing different rFVIII concentrates as a source of FVIII and enzyme-linked immunosorbent assay to search for anti-PEG antibodies. Results We found inhibitory anti-PEG/anti-PEGylated rFVIII antibodies in 4 patients (5%), both persistent and transient, explaining the impaired recovery. The patients had neutralizing anti-PEG antibodies prior to the first dosing of PEGylated rFVIII. We demonstrated neutralizing antibodies (mainly immunoglobuline G) specific for PEG and all 3 commercially available PEGylated rFVIII products. Conclusion The number of patients with inhibitory anti-PEG antibodies was significant, and the presence of inhibitors against PEGylated rFVIII emphasizes the importance of individual monitoring when switching FVIII concentrates to ensure safety and efficacy of the treatment.
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Imbery, John Franklin; Heinzelbecker, Julia; Jebsen, Jenny Karoline; McGowan, Marc Kevin; Myklebust, Camilla Victoria & Bottini, Nunzio
[Show all 13 contributors for this article]
(2022).
T-helper cell regulation of CD45 phosphatase activity by galectin-1 and CD43 governs chronic lymphocytic leukaemia proliferation.
British Journal of Haematology.
ISSN 0007-1048.
198(3),
p. 556–573.
doi:
10.1111/bjh.18285.
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Chronic lymphocytic leukaemia (CLL) is characterised by malignant mature-like B cells. Supportive to CLL cell survival is chronic B-cell receptor (BCR) signalling; however, emerging evidence demonstrates CLL cells proliferate in response to T-helper (Th) cells in a CD40L-dependent manner. We showed provision of Th stimulation via CD40L upregulated CD45 phosphatase activity and BCR signalling in non-malignant B cells. Consequently, we hypothesised Th cell upregulation of CLL cell CD45 activity may be an important regulator of CLL BCR signalling and proliferation. Using patient-derived CLL cells in a culture system with activated autologous Th cells, results revealed increases in both Th and CLL cell CD45 activity, which correlated with enhanced downstream antigen receptor signalling and proliferation. Concomitantly increased was the surface expression of Galectin-1, a CD45 ligand, and CD43, a CLL immunophenotypic marker. Galectin-1/CD43 double expression defined a proliferative CLL cell population with enhanced CD45 activity. Targeting either Galectin-1 or CD43 using silencing, pharmacology, or monoclonal antibody strategies dampened CD45 activity and CLL cell proliferation. These results highlight a mechanism where activated Th cells drive CLL cell BCR signalling and proliferation via Galectin-1 and CD43-mediated regulation of CD45 activity, identifying modulation of CD45 phosphatase activity as a potential therapeutic target in CLL.
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Berentsen, Sigbjørn & Tjønnfjord, Geir Erland
(2022).
Current Treatment Options in Cold Agglutinin Disease: B-Cell Directed or Complement Directed Therapy?
Transfusion Medicine Reviews.
ISSN 0887-7963.
36(4),
p. 181–187.
doi:
10.1016/j.tmrv.2022.05.001.
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Two major steps are identified in the pathogenesis of cold agglutinin disease; clonal B-cell lymphoproliferation and complement-mediated hemolysis. Each of these steps constitutes a target for treatment. In this focused review, we address 2 successful therapeutic approaches; the bendamustine plus rituximab combination as a highly efficacious B-cell directed therapy and the anti-C1s monoclonal antibody sutimlimab as the most extensively studied complement-targeting therapy. We describe and discuss the prospective study of bendamustine plus rituximab and 2 recent, prospective studies of sutimlimab. Bendamustine-rituximab results in a high response rate, frequent complete responses and long median response duration, and the treatment is temporary. However, this therapy is relatively slow-acting and associated with some toxicity. Sutimlimab is also highly efficacious, is far more rapidly acting, and is low-toxic. Disadvantages of sutimlimab are the lack of effect on circulatory symptoms, the probable need for indefinite treatment, and the very high costs. In cold agglutinin disease patients who require treatment, the choice should be based on an individual assessment.
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Yin, Yanping; Athanasiadis, Paschalis; Karlsen, Linda; Urban, Aleksandra; Xu, Haifeng & Murali, Ishwarya
[Show all 17 contributors for this article]
(2022).
Functional testing to characterize and stratify PI3K inhibitor responses in chronic lymphocytic leukemia.
Clinical Cancer Research.
ISSN 1078-0432.
28(20),
p. 4444–4455.
doi:
10.1158/1078-0432.CCR-22-1221.
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Purpose:
PI3K inhibitors (PI3Ki) are approved for relapsed chronic lymphocytic leukemia (CLL). Although patients may show an initial response to these therapies, development of treatment intolerance or resistance remain clinical challenges. To overcome these, prediction of individual treatment responses based on actionable biomarkers is needed. Here, we characterized the activity and cellular effects of 10 PI3Ki and investigated whether functional analyses can identify treatment vulnerabilities in PI3Ki-refractory/intolerant CLL and stratify responders to PI3Ki.
Experimental Design:
Peripheral blood mononuclear cell samples (n = 51 in total) from treatment-naïve and PI3Ki-treated patients with CLL were studied. Cells were profiled against 10 PI3Ki and the Bcl-2 antagonist venetoclax. Cell signaling and immune phenotypes were analyzed by flow cytometry. Cell viability was monitored by detection of cleaved caspase-3 and the CellTiter-Glo assay.
Results:
pan-PI3Kis were most effective at inhibiting PI3K signaling and cell viability, and showed activity in CLL cells from both treatment-naïve and idelalisib-refractory/intolerant patients. CLL cells from idelalisib-refractory/intolerant patients showed overall reduced protein phosphorylation levels. The pan-PI3Ki copanlisib, but not the p110δ inhibitor idelalisib, inhibited PI3K signaling in CD4+ and CD8+ T cells in addition to CD19+ B cells, but did not significantly affect T-cell numbers. Combination treatment with a PI3Ki and venetoclax resulted in synergistic induction of apoptosis. Analysis of drug sensitivities to 73 drug combinations and profiling of 31 proteins stratified responders to idelalisib and umbralisib, respectively.
Conclusions:
Our findings suggest novel treatment vulnerabilities in idelalisib-refractory/intolerant CLL, and indicate that ex vivo functional profiling may stratify PI3Ki responders.
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Jønsson, Viggo; Awan, Haneef; Jones, Neil Deaton; Johannessen, Tom Børge; Thøgersen, Klaus & Steig, Bjarni á
[Show all 8 contributors for this article]
(2022).
Meiotic drive in chronic lymphocytic leukemia compared with other malignant blood disorders.
Scientific Reports.
12:6138(1),
p. 1–11.
doi:
10.1038/s41598-022-09602-1.
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Abstract The heredity of the malignant blood disorders, leukemias, lymphomas and myeloma, has so far been largely unknown. The present study comprises genealogical investigations of one hundred and twelve Scandinavian families with unrelated parents and two or more cases of malignant blood disease. For comparison, one large family with related family members and three hundred and forty-one cases of malignant blood disease from the Faroese population was included. The inheritance is non-Mendelian, a combination of genomic parental imprinting and feto-maternal microchimerism. There is significantly more segregation in maternal than in paternal lines, predominance of mother-daughter combinations in maternal lines, and father-son combinations in paternal lines. Chronic lymphocytic leukemia is the most frequent diagnosis in the family material, and chronic lymphocytic leukemia has a transgenerational segregation that is unique in that inheritance of susceptibility to chronic lymphocytic leukemia is predominant in males of paternal lines. Male offspring with chronic lymphocytic leukemia in paternal lines have a birth-order effect, which is manifest by the fact that there are significantly more male patients late in the sibling line. In addition, there is contravariation in chronic lymphocytic leukemia, i.e. lower occurrence than expected in relation to other diagnoses, interpreted in such a way that chronic lymphocytic leukemia remains isolated in the pedigree in relation to other diagnoses of malignant blood disease. Another non-Mendelian function appears in the form of anticipation, i.e. increased intensity of malignancy down through the generations and a lower age at onset of disease than otherwise seen in cases from the Cancer Registers, in acute lymphoblastic leukemia, for example. It is discussed that this non-Mendelian segregation seems to spread the susceptibility genes depending on the gender of the parents and not equally to all children in the sibling line, with some remaining unaffected by susceptibility i.e. "healthy and unaffected", due to a birth order effect. In addition, anticipation is regarded as a non-Mendelian mechanism that can amplify, «preserve» these vital susceptibility genes in the family. Perhaps this segregation also results in a sorting of the susceptibility, as the percentage of follicular lymphoma and diffuse large B-cell lymphoma is lower in the family material than in an unselected material. Although leukemias, lymphomas and myelomas are potentially fatal diseases, this non-Mendelian distribution and amplification hardly play any quantitative role in the survival of Homo sapiens, because these diseases mostly occur after fertile age.
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Skånland, Sigrid S & Tjønnfjord, Geir Erland
(2022).
Determining drug dose in the era of targeted therapies: playing it (un)safe?
Blood Cancer Journal.
12(8).
doi:
10.1038/s41408-022-00720-7.
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Abstract Targeted therapies against phosphatidylinositol 3-kinase (PI3K), Bruton’s tyrosine kinase (BTK), and B-cell lymphoma-2 (BCL-2) are approved for chronic lymphocytic leukemia (CLL). Since approval of the first-in-class drugs, next-generation agents have become available and are continuously under development. While these therapies act on well-characterized molecular targets, this knowledge is only to some extent taken into consideration when determining their dose in phase I trials. For example, BTK occupancy has been assessed in dose-finding studies of various BTK inhibitors, but the minimum doses that result in full BTK occupancy were not determined. Although targeted agents have a different dose–response relationship than cytotoxic agents, which are more effective near the maximum tolerated dose, the traditional 3 + 3 toxicity-driven trial design remains heavily used in the era of targeted therapies. If pharmacodynamic biomarkers were more stringently used to guide dose selection, the recommended phase II dose would likely be lower as compared to the toxicity-driven selection. Reduced drug doses may lower toxicity, which in some cases is severe for these agents, and are supported by retrospective studies demonstrating non-inferior outcomes for patients with clinically indicated dose reductions. Here, we review strategies that were used for dose selection in phase I studies of currently approved and select investigational targeted therapies in CLL, and discuss how our initial clinical experience with targeted therapies have pointed to dose reductions, intermittent dosing, and drug combinations as strategies to overcome treatment intolerance and resistance.
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Solhaug, Terje Singsaas; Tjønnfjord, Geir Erland; BJØRGO, KATHRINE & Kildahl-Andersen, Odd A
(2022).
A family with cytotoxic T-lymphocyte-associated protein 4 haploinsufficiency presenting with aplastic anaemia.
BMJ Case Reports.
15(2).
doi:
10.1136/bcr-2021-247653.
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Haroun-Izquierdo, Alvaro; Vincenti, Marianna; Netskar, Herman Krogstad; Ooijen, Hanna van; Zhang, Bin & Bendzick, Laura
[Show all 30 contributors for this article]
(2022).
Adaptive single-KIR+NKG2C+ NK cells expanded from select superdonors show potent missing-self reactivity and efficiently control HLA-mismatched acute myeloid leukemia.
Journal for ImmunoTherapy of Cancer (JITC).
10:e005577(11),
p. 1–13.
doi:
10.1136/jitc-2022-005577.
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Background Natural killer (NK) cells hold great promise as a source for allogeneic cell therapy against hematological malignancies, including acute myeloid leukemia (AML). Current treatments are hampered by variability in NK cell subset responses, a limitation which could be circumvented by specific expansion of highly potent single killer immunoglobulin-like receptor (KIR)+NKG2C+ adaptive NK cells to maximize missing-self reactivity. Methods We developed a GMP-compliant protocol to expand adaptive NK cells from cryopreserved cells derived from select third-party superdonors, that is, donors harboring large adaptive NK cell subsets with desired KIR specificities at baseline. We studied the adaptive state of the cell product (ADAPT-NK) by flow cytometry and mass cytometry as well as cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq). We investigated the functional responses of ADAPT-NK cells against a wide range of tumor target cell lines and primary AML samples using flow cytometry and IncuCyte as well as in a mouse model of AML. Results ADAPT-NK cells were >90% pure with a homogeneous expression of a single self-HLA specific KIR and expanded a median of 470-fold. The ADAPT-NK cells largely retained their adaptive transcriptional signature with activation of effector programs without signs of exhaustion. ADAPT-NK cells showed high degranulation capacity and efficient killing of HLA-C/KIR mismatched tumor cell lines as well as primary leukemic blasts from AML patients. Finally, the expanded adaptive NK cells had preserved robust antibody-dependent cellular cytotoxicity potential and combination of ADAPT-NK cells with an anti-CD16/IL-15/anti-CD33 tri-specific engager led to near-complete killing of resistant CD45dim blast subtypes. Conclusions These preclinical data demonstrate the feasibility of off-the-shelf therapy with a non-engineered, yet highly specific, NK cell population with full missing-self recognition capability.
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Giliberto, Mariaserena; Raj, Deepak Balaji Thimiri Govinda; Cremaschi, Andrea; Skånland, Sigrid S; Gade, Alexandra & Tjønnfjord, Geir Erland
[Show all 9 contributors for this article]
(2022).
Ex vivo drug sensitivity screening in multiple myeloma identifies drug combinations that act synergistically.
Molecular Oncology.
ISSN 1574-7891.
16(6),
p. 1241–1258.
doi:
10.1002/1878-0261.13191.
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The management of multiple myeloma (MM) is challenging: An assortment of available drug combinations adds complexity to treatment selection, and treatment resistance frequently develops. Given the heterogeneous nature of MM, personalized testing tools are required to identify drug sensitivities. To identify drug sensitivities in MM cells, we established a drug testing pipeline to examine ex vivo drug responses. MM cells from 44 patients were screened against 30 clinically relevant single agents and 44 double- and triple-drug combinations. We observed variability in responses across samples. The presence of gain(1q21) was associated with low sensitivity to venetoclax, and decreased ex vivo responses to dexamethasone reflected the drug resistance observed in patients. Less heterogeneity and higher efficacy was detected with many combinations compared to the corresponding single agents. We identified new synergistic effects of melflufen plus panobinostat using low concentrations (0.1–10 nm and 8 nm, respectively). In agreement with clinical studies, clinically approved combinations, such as triple combination of selinexor plus bortezomib plus dexamethasone, acted synergistically, and synergies required low drug concentrations (0.1 nm bortezomib, 10 nm selinexor and 4 nm dexamethasone). In summary, our drug screening provided results within a clinically actionable 5-day time frame and identified synergistic drug efficacies in patient-derived MM cells that may aid future therapy choices.
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Cui, Xueyan; Tjønnfjord, Geir Erland; Kanse, Sandip; Dahm, Anders Erik A; Iversen, Nina & Myklebust, Christiane Filion
[Show all 12 contributors for this article]
(2021).
Tissue factor pathway inhibitor upregulates CXCR7 expression and enhances CXCL12-mediated migration in chronic lymphocytic leukemia.
Scientific Reports.
11.
doi:
10.1038/s41598-021-84695-8.
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Abstract The infiltration of chronic lymphocytic leukemia (CLL) cells into lymphoid organs correlates with disease severity. CXCL12 is a key chemotactic factor for the trafficking of CLL. Tissue factor pathway inhibitor (TFPI) is a serine protease inhibitor and plays a role in CXCL12-mediated hematopoietic stem cell homing. We aim to explore the role of TFPI in CXCL12-mediated migration of CLL cells. In this study, plasma TFPI concentrations were measured by ELISA. CLL cells were isolated from patients and used for trans-endothelial migration (TEM) assays. Quantitative RT-PCR and Western blotting were used to detect the expression of CXCR7, CXCR4 and β-catenin. Immunofluorescence and co-immunoprecipitation was used to detect the binding of TFPI and glypican-3 (GPC3). We found that plasma TFPI levels in CLL patients were higher than in healthy controls, particularly in the patients with advanced disease. TFPI enhanced CXCL12-mediated TEM of CLL cells by increasing the expression of the CXCL12 receptor CXCR7, but not of the CXCL12 receptor CXCR4. The effect of TFPI on TEM was abolished by the CXCR7 inhibitor, CCX771, while the CXCR4 inhibitor AMD3100 strongly increased TEM. TFPI co-localized with GPC3 on the cell surface. An antibody to GPC3, HS20, decreased CXCR7 expression and abolished the effect of TFPI on TEM. TFPI activated β-catenin and the Wnt/β-catenin inhibitor IWP4 repressed the effect of TFPI on CXCR7 expression and TEM. We conclude that TFPI may contribute to organ infiltration in CLL patients.
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Ali, Maryan Mohamed; Grønvold, Bjørn Christer Linder; Remberger, Mats; Abrahamsen, Ingerid Weum; Myhre, Anders Eivind & Tjønnfjord, Geir Erland
[Show all 8 contributors for this article]
(2021).
Addition of Anti-thymocyte Globulin in Allogeneic Stem Cell Transplantation With Peripheral Stem Cells From Matched Unrelated Donors Improves Graft-Versus-Host Disease and Relapse Free Survival.
Clinical Lymphoma, Myeloma & Leukemia.
ISSN 2152-2650.
21(9),
p. 598–605.
doi:
10.1016/j.clml.2021.05.003.
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Anti-thymocyte globulin (ATG) is commonly used to prevent graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). To evaluate the impact of ATG as part of the GvHD prophylaxis in our institution, we report the outcome of 415 patients with matched unrelated donors (MUD) transplanted for hematological malignancies with or without ATG from 2005 to 2019 at Oslo University Hospital, Norway. The following groups were compared: (1) 154 patients transplanted with peripheral blood stem cells (PBSC) without ATG 2005-2014. (2) 137 patients transplanted with bone marrow stem cells (BMSC) 2005-2019. (3) 124 patients transplanted with PBSC and ATG (PBSC + ATG) 2014-2019. Three years survival was similar in the groups, 61% following allografting with PBSC, 54% with BMSC, and 59% with PBSC + ATG. Acute GvHD grade III-IV was 14%, 14%, and 7%; chronic GvHD was 81%, 32, and 26%; and extensive cGvHD 44%, 15%, and 6% in the corresponding groups. Both acute and chronic GvHD were significantly reduced in the PBSC + ATG-versus the PBSC group (p < 0.05 and p < 0.001 respectively).Transplant-related mortality (TRM) was 33%, 25%, and 17% (p = 0.18). Graft versus host disease and relapse free survival (GRFS) at 3 years was 43 %, 43%, and 64% in the groups. Adding ATG to the GvHD prophylaxis regimen of MUD allo-HSCT with PBSC resulted in a substantial reduction of both acute and chronic GvHD without compromising the disease control, reflected in a superior 3 years GRFS.
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Ali, Muhammad; Giannakopoulou, Eirini Chrysovalantou; Li, Yingqian; Lehander, Madeleine; Culleton, Stina Virding & Yang, Weiwen
[Show all 33 contributors for this article]
(2021).
T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes.
Nature Biotechnology.
ISSN 1087-0156.
doi:
10.1038/s41587-021-01089-x.
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Abstract Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80–94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes.
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Tjønnfjord, Geir Erland; Schjesvold, Fredrik Hellem; Gulbrandsen, Nina & Kvam, Ann Kristin
(2021).
Monoklonal gammopati av klinisk betydning.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
141(13),
p. 1–9.
doi:
10.4045/tidsskr.20.0981.
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Monoklonal gammopati er hyppig og kan være assosiert med alvorlig sykdom, men målrettet behandling kan gi betydelig helsegevinst. Det er godt kjent at funn av monoklonal gammopati bør føre til en vurdering om pasienten kan ha myelomatose eller annen B-lymfoproliferativ sykdom, men at det monoklonale immunglobulinet direkte kan føre til sykdom, er langt mindre kjent.
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Mirlashari, Mohammad Reza; Vetlesen, Annette; Nissen-Meyer, Lise Sofie Haug; Naper, Christian; Tjønnfjord, Geir Erland & Njerve, Ida Unhammer
[Show all 12 contributors for this article]
(2021).
HLA class I depletion by citric acid, and irradiation of
apheresis platelets for transfusion of refractory patients.
Transfusion.
ISSN 0041-1132.
61(4),
p. 1222–1234.
doi:
10.1111/trf.16282.
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Background Patients can form antibodies to foreign human leukocyte antigen (HLA) Class I antigens after exposure to allogeneic cells. These anti‐HLA class I antibodies can bind transfused platelets (PLTs) and mediate their destruction, thus leading to PLT refractoriness. Patients with PLT refractoriness need HLA‐matched PLTs, which require expensive HLA typing of donors, antibody analyses of patient sera and/or crossmatching. An alternative approach is to reduce PLT HLA Class I expression using a brief incubation in citric acid on ice at low pH. Methods and Materials Apheresis PLT concentrates were depleted of HLA Class I complexes by 5 minutes incubation in ice‐cold citric acid, at pH 3.0. Surface expression of HLA Class I complexes, CD62P, CD63, phosphatidylserine, and complement factor C3c was analyzed by flow cytometry. PLT functionality was tested by thromboelastography (TEG). Results Acid treatment reduced the expression of HLA Class I complexes by 71% and potential for C3c binding by 11.5‐fold compared to untreated PLTs. Acid‐treated PLTs were significantly more activated than untreated PLTs, but irrespective of this increase in steady‐state activation, CD62P and CD63 were strongly upregulated on both acid‐treated and untreated PLTs after stimulation with thrombin receptor agonist peptide. Acid treatment did not induce apoptosis over time. X‐ray irradiation did not significantly influence the expression of HLA Class I complexes, CD62P, CD63, and TEG variables on acid treated PLTs. Conclusion The relatively simple acid stripping method can be used with irradiated apheresis PLTs and may prevent transfusion‐associated HLA sensitization and overcome PLT refractoriness.
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Måseide, Ragnhild Johanne; Berntorp, Erik; Astermark, Jan; Hansen, Jessica; Olsson, Anna & Bruzelius, Maria
[Show all 11 contributors for this article]
(2021).
Haemophilia early arthropathy detection with ultrasound and haemophilia joint health score in the moderate haemophilia (MoHem) study.
Haemophilia.
ISSN 1351-8216.
27(2),
p. e253–e259.
doi:
10.1111/hae.14245.
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Introduction Detection of early arthropathy is crucial for the management of haemophilia, but data on moderate haemophilia are limited. Therefore, we evaluated joint health and treatment modalities in Nordic patients with moderate haemophilia A (MHA) and B (MHB). Aim To explore and compare the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) and Haemophilia Joint Health Score (HJHS) to detect early arthropathy in moderate haemophilia. Methods A cross-sectional, multicentre study covering Nordic patients with MHA and MHB. Arthropathy was evaluated by HEAD-US and HJHS 2.1. Results We assessed 693 joints in 118 patients. HEAD-US scores (medians [interquartile ranges]) were as follows: elbows 0 points (0–0), knees 0 (0–0) and ankles 0 (0–1). Respectively, by HJHS: elbows 0 (0–1), knees 0 (0–1) and ankles 0 (0–1). Cartilage (14%) and bone (13%) were most commonly affected by HEAD-US. Frequent HJHS findings were crepitus on motion in knees (39%), and loss of flexion (23%) and extension (13%) in ankles. HEAD-US correlated strongly with HJHS (elbows r = .70, knees r = .60 and ankles r = .65), but 24% had discordant scores. Joints with HJHS zero points, 5% captured HEAD-US ≥1 point. Moreover, 26% had HJHS findings without HEAD-US pathology. Notably, 31% of knees had crepitus on motion and normal HEAD-US. Conclusion Overall, the joints attained low scores implying good joint health. HEAD-US correlated strongly with HJHS. In 5%, HEAD-US detected subclinical pathology. Crepitus on motion was frequently reported despite normal HEAD-US, thus not necessarily reflecting arthropathy. HEAD-US therefore improves the joint assessment in moderate haemophilia.
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Remberger, Mats; Tjønnfjord, Geir Erland; Abrahamsen, Ingerid Weum; Ali, Maryan Mohamed; Myhre, Anders Eivind & Gedde-Dahl, Tobias
[Show all 7 contributors for this article]
(2021).
Superior Graft-versus-Host Disease-Free Relapse-Free Survival in Matched Unrelated Donor Hematopoietic Stem Cell Transplantation with Anti-Thymocyte Globulin (ATG) Compared to Matched Related Donor without ATG.
Transplantation and Cellular Therapy (TCT).
ISSN 2666-6375.
27(7),
p. 621.e1–621.e3.
doi:
10.1016/j.jtct.2021.03.019.
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Schultz, Nina Haagenrud; Sørvoll, Ingvild Hausberg; Michelsen, Annika; Munthe, Ludvig Andre; Lund-Johansen, Fridtjof & Ahlen, Maria Therese
[Show all 11 contributors for this article]
(2021).
Thrombosis and thrombocytopenia after CHADOX1 NCoV-19 vaccination.
New England Journal of Medicine.
ISSN 0028-4793.
384(22),
p. 2124–2130.
doi:
10.1056/NEJMoa2104882.
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We report findings in five patients who presented with venous thrombosis and thrombocytopenia 7 to 10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against coronavirus disease 2019 (Covid-19). The patients were health care workers who were 32 to 54 years of age. All the patients had high levels of antibodies to platelet factor 4–polyanion complexes; however, they had had no previous exposure to heparin. Because the five cases occurred in a population of more than 130,000 vaccinated persons, we propose that they represent a rare vaccine-related variant of spontaneous heparin-induced thrombocytopenia that we refer to as vaccine-induced immune thrombotic thrombocytopenia.
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Måseide, Ragnhild Johanne; Berntorp, Erik; Nummi, Vuokko; Lassila, Riitta; Tjønnfjord, Geir E. & Holme, Pål A.
(2021).
Bleeding phenotype of patients with moderate haemophilia A and B assessed by thromboelastometry and thrombin generation.
Haemophilia.
ISSN 1351-8216.
p. 1–10.
doi:
10.1111/hae.14355.
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Introduction Predicting the bleeding phenotype is crucial for the management of patients with moderate haemophilia. Global coagulation assays evaluate haemostasis more comprehensively than conventional methods. Aim To explore global coagulation assays and the bleeding phenotype of patients with moderate haemophilia A (MHA) and B (MHB). Methods The MoHem study is a cross-sectional, multicentre study covering Nordic patients with MHA and MHB. Thromboelastometry in whole blood and thrombin generation (TG) in platelet-poor plasma (1, 2.5 and 5 pM tissue factor (TF)) were compared with joint health (Haemophilia Joint Health Score (HJHS)) and treatment modality. Results We report on 61 patients from Oslo and Helsinki: 24 MHA and 37 MHB. By TG (2.5 pM TF), patients who had been without replacement therapy during the previous 12 months depicted higher endogenous thrombin potential (P = .03). In contrast, those who had low ETP (< median) captured higher HJHS (P = .02). Patients who had undergone orthopaedic surgery generated least thrombin (P = .02). By thromboelastometry, those without the need of factor consumption had short clotting times, and quick times to maximum velocity (< median values) (P = .03). Factor VIII/factor IX activity (FVIII/FIX:C) did not align with the bleeding phenotype, but FIX:C ≤ 3 IU/dL was associated with lower peak thrombin (P = .03). Conclusion TG differentiated patients with moderate haemophilia according to HJHS, annual factor consumption, and whether orthopaedic surgery had been performed. Thromboelastometry differentiated according to factor consumption only. Global coagulation assays may assist predicting the bleeding phenotype in moderate haemophilia.
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Melvold, Katrine; Giliberto, Mariaserena; Karlsen, Linda; Ayuda-Duran, Maria del Pilar; Hanes, Robert & Holien, Toril
[Show all 11 contributors for this article]
(2021).
Mcl-1 and Bcl-xL levels predict responsiveness to dual MEK/Bcl-2 inhibition in B-cell malignancies.
Molecular Oncology.
ISSN 1574-7891.
p. 1–18.
doi:
10.1002/1878-0261.13153.
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Most patients with chronic lymphocytic leukemia (CLL) initially respond to targeted therapies, but eventually relapse and develop resistance. Novel treatment strategies are therefore needed to improve patient outcomes. Here, we performed direct drug testing on primary CLL cells and identified synergy between eight different mitogen-activated protein kinase kinase (MEK) inhibitors and the B-cell lymphoma 2 (Bcl-2) antagonist venetoclax. Drug sensitivity was independent of immunoglobulin heavy-chain gene variable region (IGVH) and tumor protein p53 (TP53) mutational status, and CLL cells from idelalisib-resistant patients remained sensitive to the treatment. This suggests that combined MEK/Bcl-2 inhibition may be an option for high-risk CLL. To test whether sensitivity could be detected in other B-cell malignancies, we performed drug testing on cell line models of CLL (n = 4), multiple myeloma (MM; n = 8), and mantle cell lymphoma (MCL; n = 7). Like CLL, MM cells were sensitive to the MEK inhibitor trametinib, and synergy was observed with venetoclax. In contrast, MCL cells were unresponsive to MEK inhibition. To investigate the underlying mechanisms of the disease-specific drug sensitivities, we performed flow cytometry-based high-throughput profiling of 31 signaling proteins and regulators of apoptosis in the 19 cell lines. We found that high expression of the antiapoptotic proteins myeloid cell leukemia-1 (Mcl-1) or B-cell lymphoma-extra large (Bcl-xL) predicted low sensitivity to trametinib + venetoclax. The low sensitivity could be overcome by combined treatment with an Mcl-1 or Bcl-xL inhibitor. Our findings suggest that MEK/Bcl-2 inhibition has therapeutic potential in leukemia and myeloma, and demonstrate that protein expression levels can serve as predictive biomarkers for treatment sensitivities.
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Skaarud, Kristin Aneta Joan; Hov, Johannes Espolin Roksund; Hansen, Simen Hyll; Kummen, Martin; Valeur, Jørgen & Seljeflot, Ingebjørg
[Show all 12 contributors for this article]
(2021).
Mortality and microbial diversity after allogenic hematopoietic stem cell transplantation: secondary analysis of a randomized nutritional intervention trial.
Scientific Reports.
11.
doi:
10.1038/s41598-021-90976-z.
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Gut mucosal barrier injury is common following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and associated with poor clinical outcomes. Diet is critical for microbial diversity, but whether nutritional support affects microbiota and outcome after allo-HSCT is unknown. We present a secondary analysis of a randomized controlled nutritional intervention trial during allo-HSCT. We investigated if the intervention influenced gut microbiota, short-chain fatty acids (SCFAs), and markers of gut barrier functions, and if these parameters were associated with clinical outcomes. Fecal specimens were available from 47 recipients, and subjected to 16S rRNA gene sequencing. We found no significant differences between the intervention group and controls in investigated parameters. We observed a major depletion of microbiota, SCFAs, and altered markers of gut barrier function from baseline to 3 weeks post-transplant. One-year mortality was significantly higher in patients with lower diversity at 3 weeks post-HSCT, but not related to diversity at baseline. The relative abundance of Blautia genus at 3 weeks was higher in survivors. Fecal propionic acid was associated with survival. Markers of gut barrier functions were less strongly associated with clinical outcomes. Possibly, other strategies than dietary intervention are needed to prevent negative effects of gut microbiota and clinical outcomes after allo-HSCT.
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Tvedt, Tor Henrik Anderson; Skaarud, Kristin Aneta Joan; Tjønnfjord, Geir Erland; Gedde-Dahl, Tobias; Iversen, Per Ole & Bruserud, Øystein
(2020).
The systemic metabolic profile early after allogeneic stem cell transplantation: Effects of adequate energy support administered through enteral feeding tube.
Biology of Blood and Marrow Transplantation.
ISSN 1083-8791.
26(2),
p. 380–391.
doi:
10.1016/j.bbmt.2019.10.005.
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Patients undergoing allogeneic stem cell transplantation usually require nutritional support. There is no consensus on whether enteral support through tube feeding should be preferred. A recent randomized study could not detect any difference between enteral and parenteral feeding with regard to post-transplant outcomes, whereas 2 retrospective studies described an association between enteral feeding and a favorable post-transplant outcome. We compared pre- and post-transplant plasma metabolomic profiles for 10 patients receiving mainly enteral nutritional support and 10 patients receiving mainly parenteral support. Samples were collected before conditioning and 3 weeks post-transplant; 824 metabolites were analyzed using mass spectrometry. The pretransplant metabolite profiles showed a significant overlap between the 2 groups. Post-transplant samples for both patient groups showed an increase of secondary bile acids and endocannabinoids, whereas reduced levels were seen for food preservatives, plasmalogens, and retinol metabolites. The main post-transplant differences between the groups were decreased levels of fatty acids and markers of mitochondrial activation in the control group, indicating that these patients had insufficient energy intake. A significant effect was also seen for heme/bilirubin metabolism for the parenteral support. To conclude, allotransplant recipients showed altered metabolic profiles early after transplantation; this was mainly due to the conditioning/transplantation/reconstitution, whereas the type of nutritional support had minor effects.
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Hetland, Geir; Tangen, Jon-Magnus; Mahmood, Faiza; Mirlashari, Mohammad Reza; Nissen-Meyer, Lise Sofie Haug & Nentwich, Ivo
[Show all 9 contributors for this article]
(2020).
Antitumor, Anti-inflammatory and Antiallergic Effects of Agaricus blazei Mushroom Extract and the Related Medicinal Basidiomycetes Mushrooms, Hericium erinaceus and Grifola frondosa: A Review of Preclinical and Clinical Studies.
Nutrients.
12(5),
p. 1–19.
doi:
10.3390/nu12051339.
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Since the 1980s, medicinal effects have been documented in scientific studies with the related Basidiomycota mushrooms Agaricus blazei Murill (AbM), Hericium erinaceus (HE) and Grifola frondosa (GF) from Brazilian and Eastern traditional medicine. Special focus has been on their antitumor effects, but the mushrooms’ anti-inflammatory and antiallergic properties have also been investigated. The antitumor mechanisms were either direct tumor attack, e.g., apoptosis and metastatic suppression, or indirect defense, e.g., inhibited tumor neovascularization and T helper cell (Th) 1 immune response. The anti-inflammatory mechanisms were a reduction in proinflammatory cytokines, oxidative stress and changed gut microbiota, and the antiallergic mechanism was amelioration of a skewed Th1/Th2 balance. Since a predominant Th2 milieu is also found in cancer, which quite often is caused by a local chronic inflammation, the three conditions—tumor, inflammation and allergy—seem to be linked. Further mechanisms for HE were increased nerve and beneficial gut microbiota growth, and oxidative stress regulation. The medicinal mushrooms AbM, HE and GF appear to be safe, and can, in fact, increase longevity in animal models, possibly due to reduced tumorigenesis and oxidation. This article reviews preclinical and clinical findings with these mushrooms and the mechanisms behind them.
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Berentsen, Sigbjørn; Malecka, Agnieszka Maria; Randen, Ulla & Tjønnfjord, Geir Erland
(2020).
Cold agglutinin disease: where do we stand, and where are we going?
Clinical Advances in Hematology & Oncology (CAH&O).
ISSN 1543-0790.
18(1),
p. 35–44.
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Berentsen, Sigbjørn; Barcellini, Wilma; D'Sa, Shirley; Randen, Ulla; Tvedt, Tor Henrik Anderson & Fattizzo, Bruno
[Show all 23 contributors for this article]
(2020).
Cold agglutinin disease revisited: a multinational, observational study of 232 patients.
Blood.
ISSN 0006-4971.
136(4),
p. 480–488.
doi:
10.1182/blood.2020005674.
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We retrospectively studied 232 patients with cold agglutinin disease (CAD) at 24 centers in 5 countries. In Norway and a northern region of Italy, the study was close to being population-based. For the first time, we demonstrate fourfold differences between cold and warmer climates regarding prevalence (20 vs 5 cases/million) and incidence (1.9 vs 0.48 cases/million per year). Mean baseline hemoglobin level was 9.3 g/dL, but 27% had hemoglobin <8 g/dL. Identification of typical features of CAD-associated lymphoproliferative disorder in the bone marrow was greatly increased by centralized biopsy assessment. CAD seems to be associated with a slightly increased risk of venous thrombosis. This work includes a follow-up study of therapies, focusing on the long-term outcomes of the rituximab plus bendamustine and rituximab plus fludarabine regimens. Rituximab plus bendamustine therapy resulted in responses in 35 (78%) of 45 patients; 24 (53%) achieved complete response. Interestingly, these rates were still higher than observed in the original (2017) prospective trial, and we also found a shift toward deeper responses with time. This is explained by the prolonged time to response seen in many patients, probably related to long-lived plasma cells. In patients responding to rituximab-bendamustine, median response duration was not reached after 88 months, and estimated 5-year sustained remission was 77%. The regimen appeared safe regarding late-occurring malignancies. Rituximab plus fludarabine therapy seems to carry a higher risk of long-term adverse effects.
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Måseide, Ragnhild Johanne; Berntorp, Erik; Astermark, Jan; Olsson, Anna; Bruzelius, Maria & Frisk, Tony
[Show all 10 contributors for this article]
(2020).
Joint health and treatment modalities in Nordic patients with moderate haemophilia A and B – The MoHem study.
Haemophilia.
ISSN 1351-8216.
26(5),
p. 891–897.
doi:
10.1111/hae.14114.
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Introduction The prevalence of arthropathy in moderate haemophilia A (MHA) and B (MHB) is not well known. Aim We evaluated joint health in Nordic patients in relation to their treatment modality. Methods A cross‐sectional, multicentre study covering MHA and MHB in Sweden, Finland and Norway. Arthropathy was evaluated by ultrasound (HEAD‐US) and Haemophilia Joint Health Score (HJHS). Results We report on 145 patients: median age 28 years (IQR 13‐52) and 61% MHA. Baseline factor VIII/factor IX activity (FVIII/FIX:C) was 2 IU/dL (median) (IQR 2‐4): lower for MHB (2 IU/dL, IQR 1‐2) than MHA (3 IU/dL, IQR 2‐4) (P < .01). Eighty‐five per cent of MHA and 73% MHB had a history of haemarthrosis (P = .07). Age at first joint bleed was lower for MHA (5 years [median], IQR 3‐7) than MHB (7 years, IQR 5‐12) (P = .01). Thirty‐eight per cent received prophylaxis, started at median 10 years of age (IQR 4‐24). Median joint bleeds and serious other bleeds during the last 12 months were both zero (IQR 0‐1). Total HEAD‐US captured 0/48 points (median) (IQR 0‐2) and HJHS 4/120 points (IQR 1‐10) with strong correlation between them (r = .72). FVIII/FIX:C ≤ 3 IU/dL was associated with higher HJHS (P = .04). Fifteen per cent had undergone orthopaedic surgery. Conclusion The current joint health in Nordic moderate haemophilia patients was rather good, but a subgroup had severe arthropathy. FVIII/FIX:C ≤ 3 IU/dL and MHA were associated with a more severe bleeding phenotype. We suggest primary prophylaxis to all patients with FVIII/FIX:C ≤ 3 IU/dL.
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Mpinganzima, Clarisse; Haaland, Alf; Holm, Anne Guro Vreim; Thein, Swee Lay; Tjønnfjord, Geir Erland & Iversen, Per Ole
(2020).
Two Consecutive Episodes of Severe Delayed Hemolytic Transfusion Reaction in a Sickle Cell Disease Patient.
Case Reports in Hematology.
ISSN 2090-6560.
doi:
10.1155/2020/2765012.
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Patients with sickle cell disease (SCD) suffer from anemia and painful vaso-occlusive crisis (VOC) and sometimes need blood transfusions. Delayed hemolytic transfusion reaction (DHTR) is a rare life-threatening complication observed in SCD and mimics VOC. We describe a female SCD patient undergoing three surgical procedures during which DHTR developed following the first two. Prior to a planned tonsillectomy, she received transfusion and three days after surgery developed severe hemolysis as well as pain and respiratory symptoms. On suspicion of VOC, she received additional transfusions and became hemodynamically unstable, and her hemolytic anemia worsened. Gradually, she recovered and could be discharged after two weeks; DHTR was not suspected. Sixteen months later, an arthroplasty was performed due to avascular necrosis, and again she was transfused preoperatively. Similar to the initial surgery, she developed symptoms and signs of VOC after three days, but this time, DHTR was suspected and further transfusions were withheld. Although immunosuppressive medication did not alleviate the condition, she improved on combined treatment with darbepoietin, rituximab, and eculizumab. Six months later, a second arthroplasty was performed uneventfully after prophylaxis with rituximab and without transfusion. DHTR should be considered in the presence of severe, unexplained hemolysis following a recent transfusion, and additional transfusions in this setting should be given only on vital indication.
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Marvyin, Kristo; Tjønnfjord, Eirik; Breland, Unni Mathilde & Tjønnfjord, Geir Erland
(2020).
Transformation to plasmablastic lymphoma in CLL upon ibrutinib treatment.
BMJ Case Reports.
13:e235816(9),
p. 1–3.
doi:
10.1136/bcr-2020-235816.
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Lenartova, Andrea; Johannessen, Tom Børge & Tjønnfjord, Geir Erland
(2020).
Chronic lymphocytic leukemia and secondary hematological malignancies: A nation-wide cancer registry study.
European Journal of Haematology.
ISSN 0902-4441.
104(6),
p. 546–553.
doi:
10.1111/ejh.13396.
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Objective Chronic lymphocytic leukemia (CLL) treatment has changed dramatically, and landscape of second hematologic malignancies (SHM) evolves in the new era of targeted therapy. No data were available about the real‐world burden of SHM. Methods All 2631 patients with CLL in the Cancer registry of Norway registered 2003‐2012 were included. Results After median follow‐up of 6.6 years, 103 patients (4%) developed SHM. Diffuse large B‐cell lymphoma (DLBCL) was most common (n = 65; 63%). Median survival was 9.3 years (95% CI; 8.9‐9.8) in non‐SHM patients and 1.7 years in DLBCL, 0.8 years in Hodgkin lymphoma (n = 12), and 2.8 years in myeloid neoplasia (n = 15; 95% CI: 0.3‐2.6, 0.6‐2.9, and 0.4‐5.3, respectively; P < .001). Outcomes were poorest for SHM patients treated for CLL (HR 2.76, 95% CI 1.4‐5.5, P = 0.003). A higher proportion of men and younger age were found in SHM patients (median age 66 vs 72 years in non‐SHM; P < .001; men 68% vs 57%, P = .03). Myeloid neoplasia was rare (incidence rate 1/1000 person‐years; 95% CI: 0.6‐1.5) and tended to occur later than DLBCL in patients treated for CLL (median time from CLL to SHM 62 vs 45 months; P = .09). Conclusions SHM and especially myeloid malignancies were rare in chemoimmunotherapy era.
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Berentsen, Sigbjørn; Roth, Alexandra; Randen, Ulla; Jilma, Bernd & Tjønnfjord, Geir Erland
(2019).
Cold agglutinin disease: Current challenges and future prospects.
Journal of Blood Medicine.
10,
p. 93–103.
doi:
10.2147/JBM.S177621.
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Abstract: Cold agglutinin disease (CAD) is a complement-dependent, classical pathway-mediated immune hemolytic disease, accounting for 15–25% of autoimmune hemolytic anemia, and at the same time, a distinct clonal B-cell lymphoproliferative disorder of the bone marrow. The disease burden is often high, but not all patients require pharmacological treatment. Several therapies directed at the pathogenic B-cells are now available. Rituximab plus bendamustine or rituximab monotherapy should be considered first-line treatment, depending on individual patient characteristics. Novel treatment options that target the classical complement pathway are under development and appear very promising, and the C1s inhibitor sutimlimab is currently being investigated in two clinical Phase II and III trials. These achievements have raised new challenges and further prospects, which are discussed. Patients with CAD requiring therapy should be considered for clinical trials.
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Skaarud, Kristin Aneta Joan; Veierød, Marit Bragelien; Lergenmuller, Simon; Bye, Asta; Iversen, Per Ole & Tjønnfjord, Geir Erland
(2019).
Body weight, body composition and survival after 1 year: follow-up of a nutritional intervention trial in allo-HSCT recipients.
Bone Marrow Transplantation.
ISSN 0268-3369.
doi:
10.1038/s41409-019-0638-6.
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The role of body weight change in survival among recipients of hematopoietic stem-cell transplantation is controversial. We assessed the effect of optimizing energy and protein intake on 1-year survival, body weight and body composition, and the effect of body weight and body composition on 1-year survival in 117 patients (57 intervention, 60 control) in a randomized controlled trial. Cox regression was used to study effects of the intervention, weight and body composition on death, relapse, and nonrelapse mortality (NRM). We found no significant effect of intervention versus control on death hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.54−2.04, p = 0.88), relapse (HR 1.15, 95% CI 0.48−2.27, p = 0.75), and NRM (HR 0.95, 95% CI 0.39−2.28, p = 0.90). Body weight, fat-free mass index, body fat mass index and total body water changed over time (p < 0.001), similarly in both groups (0.17 ≤ p ≤ 0.98). In multivariable analyses adjusted for group, gender and age, HRs and 95% CIs per one kilo increase in weight were 1.03 (1.01−1.06) and 1.04 (1.01−1.08) for death and NRM after 1 year (p ≤ 0.02), respectively, and 1.08 (1.01−1.15) for relapse after 3 months (p = 0.02). In conclusion, weight gain is possibly due to fluid retention and is an indicator of a complication in HSCT, rather than a marker of improved nutritional status.
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Jønsson, Viggo; Awan, Haneef; Jones, Neil D.; Johannessen, Tom Børge; Steig, Bjarni A & Andosdottir, Gudrid
[Show all 7 contributors for this article]
(2019).
Inheritance of Susceptibility to Malignant Blood Disorders.
Scientific Reports.
9,
p. 1–12.
doi:
10.1038/s41598-019-38879-y.
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Malignant blood disorders depend on heritable susceptibility genes and occur in familial aggregations. We suggest a model of transgenerational segregation of the susceptibility genes based on the study of malignant blood disorders in Norwegian and Danish families with unrelated parents, and in the inbred Faroese population with related parents. This model, consisting of parental genomic imprinting and mother-son microchimerism, can explain the male predominance in most of the diseases, the predominance of affected parent-offspring when parents are not related, and the different modes of segregation in males and females. The model displays a specific pattern in the distribution of affected relatives for each diagnosis, viz. a characteristic distribution in the pedigrees of family members with malignant blood disorder related to the proband. Three such patterns, each reflecting a specific transgenerational passage, were identified: (1) alterations in the number of affected relatives in paternal lines alone, e.g. in patterns for probands with multiple myeloma; (2) alterations in the number of affected relatives in both paternal and maternal lines for probands with chronic lymphocytic leukemia; and (3) no alterations in the numbers of male and female affected relatives in the parental lines, e.g. for probands with some types of malignant lymphoma.
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Andersen, May-Linn Fauske; Holme, Pål Andre & Tjønnfjord, Geir Erland
(2019).
Kirurgiske inngrep hos pasienter med alvorlig blødersykdom 1997–2014.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
139(8),
p. 709–712.
doi:
10.4045/tidsskr.18.0592.
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BAKGRUNN
Som følge av god medisinsk behandling er forventet levealder hos pasienter med alvorlig blødersykdom nå nærmest normal. Det medfører et økende behov for behandling av sykdom relatert til livsstil og økt levealder. Vi beskriver kirurgi hos pasienter med alvorlig blødersykdom i perioden 1997–2014.
MATERIALE OG METODE
Data ble hentet fra registeret knyttet til Nasjonal behandlingstjeneste for kirurgi, intervensjon og avansert diagnostikk ved blødersykdom. Pasientene ble kategorisert etter type blødersykdom og type inngrep i ortopediske og ikke-ortopediske kirurgiske inngrep.
RESULTATER
825 kirurgiske inngrep ble utført hos 286 pasienter. Antall inngrep økte fra 21 i 1997 til 66 i 2014. Økningen var knyttet til ikke-ortopediske inngrep: Det ble utført 4 slike inngrep i 1997 og 45 i 2014. Antall ortopediske inngrep varierte en del fra år til år, men viste ingen tydelig trend.
FORTOLKNING
Med økende levealder sees et økende behov for behandling av sykdommer som ikke er kausalt relatert til blødersykdom. Leger med liten erfaring med pasienter med alvorlig blødersykdom vil måtte forholde seg til sykdom relatert til livsstil og alderdom hos denne pasientgruppen.
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Torkildsen, Synne; Gorunova, Ludmila; Heim, Sverre; Tjønnfjord, Geir Erland; Spetalen, Signe & Risberg, Bente
[Show all 8 contributors for this article]
(2019).
Molecular Genetic Characterization of Acute Myeloid Leukemia With Trisomy 4 as the Sole Chromosome Abnormality.
Cancer Genomics & Proteomics.
ISSN 1109-6535.
16(3),
p. 175–178.
doi:
10.21873/cgp.20123.
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Background/Aim: The aim of the study was to determine the genetic and molecular consequences of trisomy 4, a recurrent but rare chromosomal abnormality in acute myeloid leukemia (AML). Materials and Methods: Interphase fluorescence in situ hybridization, reverse transcriptase-quantitative polymerase chain reaction for 28 chromosomal gene translocations/fusion genes, and targeted sequencing analyses were performed on five AMLs with trisomy 4 as the sole chromosomal anomaly. Results: An NPM1 frameshift mutation was found in all leukemic bone marrows, DNMT3A, FLT3, and IDH1 mutations were found in three, KIT and NRAS mutations in two, whereas IDH2 (R140Q), RUNX1, and WT1 mutations were found in only one patient each. The three patients with a DNMT3A (R882H) mutation have died. In contrast, the two patients whose leukemic cells were without this mutation, are alive 55 and 31 months after diagnosis, respectively. Conclusion: The results suggest a possible association between trisomy 4 and additional mutations that may influence prognosis.
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Lenartova, Andrea; Randen, Ulla; Johannessen, Tom Børge & Tjønnfjord, Geir Erland
(2019).
Richter syndrome epidemiology in a large population based chronic lymphocytic leukemia cohort from Norway.
Cancer Epidemiology.
ISSN 1877-7821.
60,
p. 128–133.
doi:
10.1016/j.canep.2019.04.002.
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Gamage, Thilini Hansamali Gamage Yaddehi; Gunnes, Gjermund; Lee, Robert Hugh; Louch, William Edward; Holmgren, Asbjørn & Bruton, Joseph D.
[Show all 19 contributors for this article]
(2018).
STIM1 R304W causes muscle degeneration and impaired platelet activation in mice.
Cell Calcium.
ISSN 0143-4160.
76,
p. 87–100.
doi:
10.1016/j.ceca.2018.10.001.
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STIM1 and ORAI1 regulate store-operated Ca2+ entry (SOCE) in most cell types, and mutations in these proteins have deleterious and diverse effects. We established a mouse line expressing the STIM1 R304 W gain-of-function mutation causing Stormorken syndrome to explore effects on organ and cell physiology. While STIM1 R304 W was lethal in the homozygous state, surviving mice presented with reduced growth, skeletal muscle degeneration, and reduced exercise endurance. Variable STIM1 expression levels between tissues directly impacted cellular SOCE capacity. In contrast to patients with Stormorken syndrome, STIM1 was downregulated in fibroblasts from Stim1R304W/R304W mice, which maintained SOCE despite constitutive protein activity. In studies using foetal liver chimeras, STIM1 protein was undetectable in homozygous megakaryocytes and platelets, resulting in impaired platelet activation and absent SOCE. These data indicate that downregulation of STIM1 R304 W effectively opposes the gain-of-function phenotype associated with this mutation, and highlight the importance of STIM1 in skeletal muscle development and integrity.
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Habberstad, Andreas Hanssønn; Tran, Hoa Thi Tuyet; Randen, Ulla; Spetalen, Signe; Dybedal, Ingunn & Tjønnfjord, Geir Erland
[Show all 7 contributors for this article]
(2018).
Neutropenia caused by hairy cell leukemia in a patient with myelofibrosis secondary to polycythemia vera: A case report.
Journal of Medical Case Reports.
12(1).
doi:
10.1186/s13256-018-1663-6.
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Background Polycythemia vera is a myeloproliferative disease that sometimes evolves to myelofibrosis, causing splenomegaly and neutropenia. In this case report, we describe a patient with polycythemia vera and unexplained neutropenia who later turned out to also have hairy cell leukemia. Case presentation A middle-aged Caucasian man with polycythemia vera presented to our hospital with chronic mouth ulcers. Later he developed leukopenia and pancytopenia. Bone marrow biopsies showed fibrosis. Further morphological analyses of bone marrow and blood smears revealed probable transformation into acute myeloid leukemia. However, there were also cells indicating hairy cell leukemia. Morphological and immunohistochemical analyses later confirmed the presence of hairy cell leukemia in biopsies that had been present for 3 years. Treatment with cladribine temporarily reversed the patient’s neutropenia. Conclusions Hairy cell leukemia may mimic development to myelofibrosis in patients with polycythemia vera.
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Hermansen, Johanne Uthus; Tjønnfjord, Geir Erland; Munthe, Ludvig Andre; Tasken, Kjetil & Skånland, Sigrid Strand
(2018).
Cryopreservation of primary B cells minimally influences their signaling responses.
Scientific Reports.
8:17651,
p. 1–7.
doi:
10.1038/s41598-018-36121-9.
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Phospho flow is a powerful approach to detect cell signaling aberrations, identify biomarkers and assess pharmacodynamics, and can be performed using cryopreserved samples. The effects of cryopreservation on signaling responses and the reproducibility of phospho flow measurements are however unknown in many cell systems. Here, B lymphocytes were isolated from healthy donors and patients with the B cell malignancy chronic lymphocytic leukemia and analyzed by phospho flow using phospho-specific antibodies targeting 20 different protein epitopes. Cells were analyzed both at basal conditions and after activation of cluster of differentiation 40 (CD40) or the B cell receptor. Pharmacodynamics of the novel pathway inhibitor ibrutinib was also assessed. At all conditions, fresh cells were compared to cryopreserved cells. Minimal variation between fresh and frozen samples was detected. Reproducibility was tested by running samples from the same donors in different experiments. The results demonstrate reproducibility across different phospho flow runs and support the use of cryopreserved samples in future phospho flow studies of B lymphocytes.
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Myhrvold, Ida Kristin; Cremaschi, Andrea; Hermansen, Johanne Uthus; Tjønnfjord, Geir Erland; Munthe, Ludvig Andre & Tasken, Kjetil
[Show all 7 contributors for this article]
(2018).
Single cell profiling of phospho-protein levels in chronic lymphocytic leukemia.
OncoTarget.
9(10),
p. 9273–9284.
doi:
10.18632/oncotarget.23949.
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Chronic lymphocytic leukemia (CLL) has a high incidence and a steeply growing prevalence in the Western world. The heterogeneity of the disease necessitates individual mapping of biology and predicted drug response in each patient as basis for administration of tailored treatments. Cell signaling aberrations may serve as biological indicators for suitable therapy. By applying phospho-specific flow cytometry, we mapped basal and induced phosphorylation levels of 20 phospho-epitopes on proteins relevant to B-cell signaling in B cells from 22 CLL patients and 25 normal controls. The signaling response of the cytostatic drugs fludarabine, doxorubicin and vincristine was also investigated. CLL cells exerted similar or lower basal phosphorylation levels compared to normal B cells, with the exception of STAT3 (pY705) which was increased. Interestingly, STAT3 inhibitors normalized the STAT3 (pY705) level and reduced cell viability. Vincristine treatment significantly modulated phosphorylation levels in CLL cells, while no effect was observed in controls or after fludarabine or doxorubicin treatment. After BCR stimulation, CLL cells showed a tendency towards impaired phosphorylation levels, significant for several of the analyzed proteins. However, the level of Akt (pS473) was more potently induced in IgHV unmutated CLL (UM-CLL) patient samples and was significantly higher than in M-CLL samples. Importantly, the PI3Kδ inhibitor idelalisib potently reversed the effect of anti-IgM on Akt (pS473). Thus, signaling aberrations could be identified by phosphoflow cytometry and aberrant signaling could be normalized by small molecule drugs. This approach can identify relevant drug targets as well as drug effects in the individual patient.
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Bjørneboe, Lars Henrik; Tjønnfjord, Geir Erland; Loraas, Arne; Bøe, Kristine; Liland, Katrine Høeg & Alfonso, Jose Hernán
(2026).
Recalcitrant Erythema Annulare Centrifugum Associated with Monoclonal Gammopathy: A Case Report of Remission after Plasma Cell-Directed Therapy.
doi:
10.1159/cde/abvag016.
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Introduction: Erythema annulare centrifugum (EAC) is a rare figurate erythema characterized by slowly expanding annular erythematous plaques with central clearing. Its pathogenesis remains incompletely understood, but associations with medications, infections, autoimmune disease, hematological disorders, and malignancy have been reported. Only a small number of cases describing EAC associated with monoclonal gammopathy have been reported. Case presentation: We report a case of chronic, treatment-refractory EAC occurring in association with immunoglobulin G-kappa monoclonal gammopathy. Plasma cell-directed therapy was initiated, followed by complete resolution of the cutaneous lesions, disappearance of the monoclonal component, and sustained remission during 18 months of follow-up. Although causality cannot be established from a single case, this observation supports a possible association between EAC and monoclonal gammopathy. Conclusion: In patients with chronic or recalcitrant EAC, evaluation for an underlying monoclonal gammopathy may be warranted, and plasma cell-directed therapy may be considered.
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Tjønnfjord, Geir Erland; Loraas, Arne; Spetalen, Signe; Osnes, Liv Toril Nygård & Tveten, Kristian
(2026).
Congenital Dyserythropoietic Anemia Type II Caused by a New
<i>SEC23B</i>
Sequence Variant.
doi:
10.1155/crh/7158943.
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Congenital dyserythropoietic anemias (CDAs) include a heterogeneous group of conditions characterized by insufficient erythropoiesis giving rise to monolinear cytopenia. Based on the morphological features of erythroblasts, three major subtypes have been established: CDA Type I, CDA Type II, and CDA Type III. CDA Type II is the most common type of CDAs, and this disease is characterized by a normocytic anemia with a normal or slightly increased reticulocyte count. The bone marrow is hypercellular with erythroid hyperplasia and binucleated erythroblasts with two nuclei at the same maturation stage. The inheritance is autosomal recessive, and the disease is caused by biallelic mutations in the SEC28B gene. More than 100 pathogenetic variants have been identified. Here, we report on three patients from Somalia with CDA Type II caused by a new SEC23B sequence variant. They came to attention and were diagnosed in early adulthood. Cases 1 and 2 had mild anemia with signs of hemolysis, and Case 3 had mild anemia with reticulocytosis. The eosin‐5‐maleimide binding test showed reduced binding in all three patients. Molecular genetics disclosed homozygosity for the sequence variant NM_006363.6:c.1580T > C p.(Leu527Ser) in the SEC23B gene. A bone marrow aspirate was performed from Case 2, and the smear disclosed morphological abnormalities typical for CDA Type II.
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Sundsbarm, Sebastian; Bye, Asta; Tjønnfjord, Geir Erland; Iversen, Per Ole & Skaarud, Kristin Aneta Joan
(2026).
Nutrition impact symptoms and nutritional status in adult allo-HSCT recipients during 1-year follow-up.
Bone Marrow Transplantation.
ISSN 0268-3369.
61(S1),
p. 1041–1098.
doi:
10.1038/s41409-026-02887-0.
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Background: Nutrition impact symptoms (NIS) are contributors to impaired nutritional status in allo-HSCT patients. However, the impact of patients’ reported NIS on nutritional status are poorly described. This study investigated changes in NIS and nutritional status, and associations between NIS and nutritional status during a 1-year follow-up of allo-HSCT patients.
Methods: We used data from 117 patients (57 intervention, 60 control) who participated in a randomized controlled nutritional intervention trial. Linear mixed models were used to analyse changes in NIS over time. Ordinal logistic regressions were used to analyse associations between NIS and nutritional status.
Results: Nausea and vomiting and constipation were significantly lower in the intervention group than the control group during 1-year follow-up (p = 0.015 and p < 0.001, respectively). Initially, nutritional status declined in both study groups post-allo-HSCT but improved over time. Significantly fewer patients in the intervention group were malnourished at 3 weeks (p = 0.020) and 6 weeks post-transplantation (p = 0.028). Associations between NIS and nutritional status varied over time and differed between the study groups at 6 weeks post-transplantation (OR 3.702, 95% CI: (1.355, 10.100), p = 0.011).
Conclusions: In conclusion, our findings emphasize the need for long term monitoring of symptoms and nutritional status in allo-HSCT patients, supporting individualized nutritional assessments as part of long-term care strategies.
Disclosure: Geir Erland Tjønnfjord has received research grants from Mundipharma and Alexion Pharmaceuticals, advisory board honoraria from Alexion Pharmaceuticals and Johnson & Johnson, and lecture honoraria from Novartis, Johnson & Johnson, Alexion Pharmaceuticals, and Mundipharma. The other authors declare no competing interest.
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Tjønnfjord, Eirik; Tveten, Kristian; Spetalen, Signe & Tjønnfjord, Geir Erland
(2025).
ANKRD26 Gene Mutation and Thrombocytopenia—Is the Risk of Malignancy Dependent on the Mutation Variant?
doi:
10.3390/hematolrep17040037.
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Background and Clinical Significance: Inherited thrombocytopenia (IT) is a heterogeneous group of disorders caused by mutations in over 45 genes. Among these, ANKRD26-related thrombocytopenia (ANKRD26-RT) accounts for a notable subset and is associated with variable bleeding tendencies and an increased risk of myeloid malignancies. However, the extent of this oncogenic risk appears to vary between specific gene variants. Understanding the genotype–phenotype relationship is essential for patient counseling and management. This report presents a multigenerational family carrying the rare c.−118C > G variant in the 5′ untranslated region of ANKRD26, contributing to the discussion on variant-specific cancer predisposition. Case Presentation: Two sisters aged 57 and 60 presented with lifelong bleeding diathesis and moderate thrombocytopenia. Their symptoms included easy bruising, menorrhagia, and excessive postoperative bleeding. Genetic testing confirmed heterozygosity for the ANKRD26 c.−118C > G variant. Bone marrow analysis revealed abnormal megakaryopoiesis without evidence of dysplasia or somatic mutations. One sister underwent major surgery without complications when managed with prophylactic hemostatic therapy. Their family history included multiple female relatives with similar symptoms, although formal testing was limited. Notably, none of the affected individuals developed hematologic malignancy, and only one developed esophageal cancer, with no current evidence linking this variant to solid tumors. Conclusions: This case underscores the importance of distinguishing between ANKRD26 variants when assessing malignancy risk. While ANKRD26-RT is associated with myeloid neoplasms, the c.−118C > G variant may confer a lower oncogenic potential. Variant-specific risk stratification and genetic counseling are crucial for optimizing surveillance and avoiding unnecessary interventions in low-risk individuals.
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Andersen, Kristin; Tjønnfjord, Geir Erland; Hestdalen, Malu Lian; Spetalen, Signe & Panagopoulos, Ioannis
(2025).
Complex Genetic Evolution and Treatment Challenges in Myeloid Neoplasms: A Case of Persistent t(2;3)(p15~23;q26)/ MECOM Rearrangement, SF3B1 Mutation, and Transient TNIP1::PDGFRB Chimera.
doi:
10.21873/cgp.20483.
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Background/Aim:
Myelodysplastic syndromes (MDSs) are clonal bone marrow disorders characterized by ineffective hematopoiesis. They are classified based on morphology and genetic alterations, with SF3B1 variants linked to favorable prognosis and MECOM rearrangements associated with poor outcomes. The combined effects of these alterations remain unclear. We report an MDS patient carrying both SF3B1 and MECOM alterations who developed transient eosinophilia accompanied by a TNIP1::PDGFRB chimera in a subset of MECOM-affected cells.
Case Report:
A 73-year-old woman was diagnosed with myeloid neoplasia with excess blasts and multilineage dysplasia (MDS-EB1). Six months later, SF3B1 mutations were identified, leading to a diagnosis of MDS-SF3B1. Despite azacitidine treatment, her condition worsened, showing hypercellular bone marrow and eosinophilia. Genetic analysis revealed a t(2;3)(p15~23;q26)/MECOM rearrangement and TNIP1::PDGFRB chimera. Imatinib eradicated eosinophilia and reduced TNIP1::PDGFRB-positive cells, but the MECOM-clone persisted. Subsequent treatments, including hydroxyurea, mercaptopurine, and low-dose cytarabine, were ineffective. FLT3 mutations and high EVI1 transcript levels were later detected. The patient succumbed to progressive disease.
Conclusion:
This case highlights the complexity of MDS and the importance of genetic abnormalities in treatment planning. Persistent MECOM rearrangement and the TNIP1::PDGFRB chimera emphasize the need for further research into resistance mechanisms.
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Andersen, Kristin; Tjønnfjord, Geir Erland; Ramslien, Lloyd Frode & Panagopoulos, Ioannis
(2024).
RUNX1::MIR99AHG Chimera in Acute Myeloid Leukemia.
Genes, Chromosomes and Cancer.
ISSN 1045-2257.
63(9).
doi:
10.1002/gcc.23272.
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RUNX1 fuses with over 70 different partner genes in hematological neoplasms. While common RUNX1 chimeras have been extensively studied and their prognosis is well established, our current understanding of less common RUNX1 chimeras is limited. Here, we present a case of acute myeloid leukemia (AML) with a rare RUNX1 chimera. Bone marrow cells obtained at diagnosis from a 71-year-old patient diagnosed with AML-M5 were studied using G-banding, fluorescence in situ hybridization, array comparative genomic hybridization, RNA sequencing, PCR, and Sanger sequencing. Combined findings from the abovementioned assays suggested three cytogenetic clones: one with a normal karyotype, one with inv(21)(q21q22), and one with two inv(21)(q21q22). The molecular analysis revealed the fusion of RUNX1 with MIR99AHG (at 21q21.1), further supporting the presence of an inv(21)(q21q22). The present case is the third reported AML harboring a RUNX1::MIR99AHG chimera. Similar to the two previously described AML patients, our case also had an FLT3 aberration.
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Kreyberg, Ina; Schrumpf, Elisabeth; Krogh, Carl Fredrik von; Lilleng, Rune & Tjønnfjord, Geir Erland
(2023).
Successful treatment of subcorneal pustular dermatosis targeting an underlying monoclonal IgA gammopathy.
Journal of the American Academy of Dermatology Case Reports.
41,
p. 33–36.
doi:
10.1016/j.jdcr.2023.08.036.
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Cui, Xueyan; Myklebust, June Helen; Munthe, Ludvig A.; Schjesvold, Fredrik Hellem; Tjønnfjord, Geir Erland & Sandset, Per Morten
[Show all 7 contributors for this article]
(2022).
Low expression of coagulation inhibitors in the immune microenvironment in precursor stages of multiple myeloma.
Research and Practice in Thrombosis and Haemostasis (RPTH).
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Helland, Åslaug; Russnes, Hege Elisabeth Giercksky; Fagereng, Gro Live; Al-Shibli, Khalid Ibrahim; Andersson, Yvonne & Berg, Thomas
[Show all 53 contributors for this article]
(2022).
Correction to: Improving public cancer care by implementing precision medicine in Norway: IMPRESS-Norway (Journal of Translational Medicine, (2022), 20, 1, (225), 10.1186/s12967-022-03432-5).
Journal of Translational Medicine.
20(1).
doi:
10.1186/s12967-022-03518-0.
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Midtvedt, Øyvind; Stray-Pedersen, Asbjørg; Andersson, Anna Helena; Gunnarsson, Ragnar; Tveten, Kristian & Ali, Maryan Mohamed
[Show all 7 contributors for this article]
(2022).
En mann i 6o-årene med kondritt og benmargssvikt.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
142(4).
doi:
10.4045/tidsskr.21.0370.
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En mann i slutten av 60-årene med terapiresistent relapserende polykondritt og benmargssvikt viste seg å ha et sjeldent og nyoppdaget syndrom som tidligere ikke er beskrevet i Norge. En mann i slutten av 60-årene ble overført til et universitetssykehus med spørsmål om underliggende revmatologisk sykdom. Han hadde seks måneders sykehistorie med redusert allmenntilstand, brystsmerter og episoder med iridosyklitt. I tillegg klaget han over smerter i bakhodet og forbigående smerter i kjeveledd ved tygging. Han hadde ingen synsforstyrrelser eller smerter i bevegelsesapparatet. Tidligere utredning med biopsi av høyre og venstre arteria temporalis viste normale funn. CT collum, thorax, abdomen og bekken viste ingen lymfeknutepatologi, men en uspesifikk fortetning basalt i venstre lunge. Prokalsitoninverdien var normal, og det var ingen oppvekst i blodkultur. Behandling med doksysyklin i 14 dager hadde ikke hatt effekt. CT aorta viste tegn på veggfortykkelse i venstre arteria subclavia. Blodprøver viste forhøyede verdier av akuttfasereaktanter (tabell 1), noe som ga mistanke om vaskulitt.
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Helland, Åslaug; Russnes, Hege Elisabeth Giercksky; Fagereng, Gro Live; Al-Shibli, Khalid Ibrahim; Andersson, Yvonne & Berg, Thomas
[Show all 53 contributors for this article]
(2022).
Improving public cancer care by implementing precision medicine in Norway: IMPRESS-Norway.
Journal of Translational Medicine.
20(1),
p. 1–11.
doi:
10.1186/s12967-022-03432-5.
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Background
Matching treatment based on tumour molecular characteristics has revolutionized the treatment of some cancers and has given hope to many patients. Although personalized cancer care is an old concept, renewed attention has arisen due to recent advancements in cancer diagnostics including access to high-throughput sequencing of tumour tissue. Targeted therapies interfering with cancer specific pathways have been developed and approved for subgroups of patients. These drugs might just as well be efficient in other diagnostic subgroups, not investigated in pharma-led clinical studies, but their potential use on new indications is never explored due to limited number of patients.
Methods
In this national, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled in multiple parallel cohorts. Each cohort is defined by the patient’s tumour type, molecular profile of the tumour, and study drug. Treatment outcome in each cohort is monitored by using a Simon two-stage-like ‘admissible’ monitoring plan to identify evidence of clinical activity.
All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Molecular diagnostics are funded by the public health care system.
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Tvedt, Tor Henrik Anderson; Steien, Egil; Øvrebø, Bente; Haaverstad, Rune; Hobbs, William & Wardęcki, Marek
[Show all 8 contributors for this article]
(2022).
Sutimlimab, an investigational C1s inhibitor, effectively prevents exacerbation of hemolytic anemia in a patient with cold agglutinin disease undergoing major surgery.
American Journal of Hematology.
ISSN 0361-8609.
97(2),
p. E51–E54.
doi:
10.1002/ajh.26409.
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Tjønnfjord, Sara Kristina Viberg; Tjønnfjord, Eirik; Konopski, Zbigniew & Tjønnfjord, Geir Erland
(2021).
Successful Control of Hepatitis B Virus Reactivation following Restart of Ibrutinib in Chronic Lymphocytic Leukaemia.
Case Reports in Hematology.
ISSN 2090-6560.
2021:1862446,
p. 1–4.
doi:
10.1155/2021/1862446.
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Ibrutinib is a targeted therapy drug that blocks the activity of Bruton’s tyrosine kinase, and it is an approved treatment for several mature B-cell malignancies including chronic lymphocytic leukaemia (CLL). Side effects include infections, cytopenia, nausea, and diarrhoea. In this report, we describe a case of hepatitis B reactivation in a female CLL patient undergoing treatment with ibrutinib. Diagnosis was confirmed with highly elevated hepatitis B virus DNA and a prior blood sample confirmed previous exposure. Ibrutinib was paused, and antiviral therapy was initiated with prompt clinical improvement. Ibrutinib was reinitiated shortly after clinical improvement. Thus, our case report demonstrates that systematic HBV screening is essential before starting treatment with ibrutinib. We suggest that antiviral prophylaxis is considered for patients at risk of reactivation, and ibrutinib may be continued following HBV reactivation with proper antiviral treatment.
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Cui, Xueyan; Tjønnfjord, Geir Erland; Kanse, Sandip; Iversen, Nina; Dahm, Anders Erik A & Myklebust, Christiane Filion
[Show all 11 contributors for this article]
(2019).
Tissue factor pathway inhibitor enhances transendothelial migration of chronic lymphocytic leukemia cells trhough CXCL12/CXCR7 chemotaxis.
Research and Practice in Thrombosis and Haemostasis (RPTH).
3.
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Published
Apr. 13, 2011 2:53 PM
- Last modified
Dec. 13, 2023 12:59 PM
