Publications by authors named "Mats Brune"

52 Publications

Vaccination against tick-borne encephalitis (TBE) after autologous and allogeneic stem cell transplantation.

Vaccine 2021 02 20;39(7):1035-1038. Epub 2021 Jan 20.

Department of Hematology and Coagulation, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address:

Introduction: Our aim was to assess response and side effects of 4 doses of TBE vaccine to patients (pts) after allo- and autologous stem cell transplantation (SCT).

Patients: Included were 104 pts with leukaemia, myeloma and lymphoma, median age 61 yrs.

Methods: Vaccine (FSME-Immun®) was given at 9, 10, 12, and 21 months post-transplant. Serum samples were obtained before and after vaccinations. Healthy controls (n = 27) received 3 vaccinations. Assessments of TBE specific IgG antibodies were performed by Enzygnost anti-TBE ELISA test (Siemens, Sweden).

Results: Antibody levels (>12 U/mL; "seropositivity") were seen in 77% and 80% of pts after allo- and autoSCT; IgG levels; 89 vs 94 U/mL. Ongoing chronic GvHD and immunosuppression (n = 29) was associated with sero-negativity in the last sample (p = 0.007). All controls (n = 27) developed protective antibody levels.

Conclusions: TBE vaccination was safe, and 4 doses starting 9 months post-SCT, induced seropositivity in a vast majority of pts.
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http://dx.doi.org/10.1016/j.vaccine.2020.12.073DOI Listing
February 2021

Complete remission after the first cycle of induction chemotherapy determines the clinical efficacy of relapse-preventive immunotherapy in acute myeloid leukaemia.

Br J Haematol 2020 02 18;188(4):e49-e53. Epub 2019 Dec 18.

TIMM Laboratory, Sahlgrenska Cancer Center, Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

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http://dx.doi.org/10.1111/bjh.16320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027927PMC
February 2020

Humoral immunity to tetanus, diphtheria and polio in adults after treatment for hematological malignancies.

Vaccine 2020 01 28;38(5):1084-1088. Epub 2019 Nov 28.

Department of Hematology and Coagulation, Institute of Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address:

Introduction: After chemotherapy, children with acute lymphocytic leukemia lose immunity and need revaccination against tetanus and diphtheria. However, little is known about immunity in adult patients after treatment for hematological malignancies. In this study, we assessed serology levels against polio, diphtheria and tetanus in adult patients after conventional treatment for leukemia and lymphoma.

Patients: One hundred and four patients, age 61 (19-86) years, were included at a median of 18 (4-77) months after chemotherapy for acute leukemia (n = 24) or lymphoma (n = 80). Pre-treatment sera were available in 73 cases for a pre-versus post treatment comparison. Healthy, age- and sex matched controls were available for 47 pts.

Methods: Tetanus antibodies were quantified using ELISA, and antibody levels ≥0.01 IU/mL were considered protective. Diphtheria antibodies were analyzed using neutralization test (n = 60) or by ELISA (n = 44). In both tests values ≥0.01 IU/mL were considered protective. Antibodies against poliovirus serotype 1 and 3 were assessed by a neutralizing test. A microneutralization titer of ≥2 was considered protective.

Results: Tetanus: There were significantly more non-immune patients after treatment (24%), compared to before (12%), p = 0.02. Post-treatment antibody levels were significantly lower than pre-treatment levels (p = 0.02). Diphtheria: There was a trend, p = 0.06, towards more non-immune patients after treatment (21%) compared to before (27%). Antibody levels post treatment were lower than pre treatment levels (p = 0.03) and lower than controls (p = 0.01). Polio: There was no significant difference in the number of non-immune patients before vs after chemotherapy for either PV1 or PV3. Protective immunity against serotype 1 and 3 was preserved in 90 and 97%, respectively.

Conclusions: After standard chemotherapy for leukemia and lymphoma a significant proportion of patients had impaired humoral immunity to diphtheria and tetanus. However, polio immunity was well preserved.
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http://dx.doi.org/10.1016/j.vaccine.2019.11.034DOI Listing
January 2020

Immunotherapy with HDC/IL-2 may be clinically efficacious in acute myeloid leukemia of normal karyotype.

Hum Vaccin Immunother 2020 24;16(1):109-111. Epub 2019 Jul 24.

TIMM Laboratory, Sahlgrenska Cancer Center, Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Immunotherapy with histamine dihydrochloride and low-dose interleukin-2 (HDC/IL-2) reduces the risk of relapse in the post-chemotherapy phase of acute myeloid leukemia (AML). Here we report the results of exploratory analyses of the clinical efficacy of HDC/IL-2 in AML with focus on the impact of karyotype aberrations in leukemic cells. Post-hoc analyses of phase III trial data suggested that HDC/IL-2 is primarily beneficial for patients with AML of normal karyotype. These results may be helpful in the selection of patients who are suitable for therapy and in the design of future immunotherapy protocols aiming at further defining the mechanism of relapse prevention by HDC/IL-2.
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http://dx.doi.org/10.1080/21645515.2019.1636598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012093PMC
March 2021

Secondary Acute Myeloid Leukemia and the Role of Allogeneic Stem Cell Transplantation in a Population-Based Setting.

Biol Blood Marrow Transplant 2019 09 6;25(9):1770-1778. Epub 2019 Jun 6.

Division of Hematology, Department of Medicine, Karolinska Institute, Stockholm, Sweden; Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Secondary AML (s-AML), including AML with an antecedent hematologic disorder (AHD-AML) and therapy-related AML (t-AML), constitutes a large proportion of patients with AML and is considered to confer a dismal prognosis. The role of allogeneic hematopoietic cell transplantation (HCT) in patients with s-AML and the extent to which HCT is performed in these patients has been little studied to date. We used the population-based Swedish AML Registry comprising 3337 intensively treated adult patients over a 17-year period to study the role of HCT within the group of patients with s-AML as well as compared with patients with de novo AML. HCT was performed in 576 patients (22%) with de novo AML, in 74 patients (17%) with AHD-AML, and in 57 patients (20%) with t-AML. At 5 years after diagnosis, there were no survivors among patients with previous myeloproliferative neoplasms who did not undergo HCT, and corresponding survival for patients with antecedent myelodysplastic syndromes and t-AML was and 2% and 4%, respectively. HCT was compared with chemotherapy consolidation in s-AML using 3 models: (1) a 200-day landmark analysis, in which HCT was favorable compared with conventional consolidation (P = .04, log-rank test); (2) a multivariable Cox regression with HCT as a time-dependent variable, in which the hazard ratio for mortality was 0.73 (95% confidence interval, 0.64 to 0.83) for HCT and favored HCT in all subgroups; and (3) a propensity score matching analysis, in which the 5-year overall survival (OS) and relapse-free survival in patients with s-AML in first complete remission (CR1) was 48% and 43%, respectively, for patients undergoing HCT versus 20% and 21%, respectively, for those receiving chemotherapy consolidation (P = .01 and .02, respectively, log-rank test). Our observational data suggest that HCT improves survival and offers the only realistic curative treatment option in patients with s-AML.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.038DOI Listing
September 2019

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

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

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

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

Allogeneic stem cell transplantation for chronic myeloid leukemia in the TKI era: population-based data from the Swedish CML registry.

Bone Marrow Transplant 2019 11 8;54(11):1764-1774. Epub 2019 Apr 8.

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

Two decades after the introduction of tyrosine kinase inhibitors (TKI), a sizeable portion of patients with chronic myeloid leukemia (CML) in chronic phase (CP) still undergo allogeneic stem cell transplantation (allo-HSCT). We investigated the indications for allo-HSCT, clinical outcome, management of relapse, and post-transplant TKI treatment in a population-based setting using the Swedish CML registry. Of 118 CML patients transplanted between 2002 and 2017, 56 (47.4%) received allo-HSCT in first CP, among whom TKI resistance was the most common transplant indication (62.5%). For patients diagnosed with CML in CP at <65 years of age, the cumulative probability of undergoing allo-HSCT within 5 years was 9.7%. Overall 5-year survival was 96.2%, 70.1% and 36.9% when transplanted in first CP, second or later CP, and in accelerated phase or blast crisis, respectively. Risk factors for relapse were EBMT score >2 and reduced intensity conditioning, and for death, CP > 2 at time point of allo-HSCT only. Non-relapse mortality for patients transplanted in CP was 11.6%. Our data indicate that allo-HSCT still constitutes a reasonable therapeutic option for patients with CML in first CP, especially those resistant to TKI treatment, providing high long-term survival and low non-relapse mortality.
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http://dx.doi.org/10.1038/s41409-019-0513-5DOI Listing
November 2019

The HLA-B -21 dimorphism impacts on NK cell education and clinical outcome of immunotherapy in acute myeloid leukemia.

Blood 2019 03 15;133(13):1479-1488. Epub 2019 Jan 15.

TIMM Laboratory at Sahlgrenska Cancer Center and.

Natural killer (NK) cell function is regulated by inhibitory receptors, such as the family of killer immunoglobulin-like receptors (KIRs) and the NKG2A/CD94 heterodimer. These receptors recognize cognate HLA class I molecules on potential target cells, and recent studies imply that an dimorphism at position -21 in the gene segment encoding the leader peptide dictates whether NK cell regulation primarily relies on the KIRs or the NKG2A/CD94 receptor. The impact of this HLA-B dimorphism on NK cell-mediated destruction of leukemic cells or on the course of leukemia is largely unknown. In a first part of this study, we compared functions of NK cells in subjects carrying HLA-B -21M or 21T using interleukin-2 (IL-2)-activated NK cells and leukemic cells from patients with acute myeloid leukemia (AML). Subjects carrying HLA-B -21M harbored better-educated NKG2A NK cells and displayed superior capacity to degranulate lytic granules against KIR ligand-matched primary leukemic blasts. Second, we aimed to define the potential impact of HLA-B -21 variation on the course of AML in a phase 4 trial in which patients received IL-2-based immunotherapy. In keeping with the hypothesis that 21M may be associated with improved NK cell functionality, we observed superior leukemia-free survival and overall survival in -21M patients than in -21T patients during IL-2-based immunotherapy. We propose that genetic variation at HLA-B -21 may determine the antileukemic efficacy of activated NK cells and the clinical benefit of NK cell-activating immunotherapy.
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http://dx.doi.org/10.1182/blood-2018-09-874990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440292PMC
March 2019

Minimal residual disease assessed with deep sequencing of NPM1 mutations predicts relapse after allogeneic stem cell transplant in AML.

Leuk Lymphoma 2019 02 2;60(2):409-417. Epub 2018 Aug 2.

a Department of Clinical Chemistry and Transfusion Medicine , Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg , Gothenburg , Sweden.

Mutations in NPM1 can be used for minimal residual disease (MRD) analysis in acute myeloid leukemia (AML). We here applied a newly introduced method, deep sequencing, allowing for simultaneous analysis of all recurrent NPM1 insertions and thus constituting an attractive alternative to multiple PCRs for the clinical laboratory. We retrospectively used deep sequencing for measurement of MRD pre- and post-allogeneic hematopoietic stem cell transplantation (alloHCT). For 29 patients in morphological remission at the time of alloHCT, the effect of deep sequencing MRD on outcome was assessed. MRD positivity was defined as variant allele frequency ≥0.02%. Post-transplant MRD status was significantly and independently associated with clinical outcome; 3-year relapse-free survival 20% vs 85% (p < .001), HR 45 (95% CI 2-1260), and overall survival 20% vs 89% (p < .001), HR 49 (95% CI 2-1253). Thus, the new methodology deep sequencing is an applicable and predictive tool for MRD assessment in AML.
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http://dx.doi.org/10.1080/10428194.2018.1485910DOI Listing
February 2019

Outcome of haematopoietic stem cell transplantation in dyskeratosis congenita.

Br J Haematol 2018 10 9;183(1):110-118. Epub 2018 Jul 9.

Haemato-Immunology Department, Robert Debre Hospital, and Paris-Diderot University, Paris, France.

Dyskeratosis congenita (DC) is a genetic multisystem disorder with frequent involvement of the bone marrow. Haematopoietic stem cell transplantation (HSCT) is the only definitive cure to restore haematopoiesis, even though it cannot correct other organ dysfunctions. We collected data on the outcome of HSCT in the largest cohort of DC (n = 94) patients ever studied. Overall survival (OS) and event-free survival (EFS) at 3 years after HSCT were 66% and 62%, respectively. Multivariate analysis showed better outcomes in patients aged less than 20 years and in patients transplanted from a matched, rather than a mismatched, donor. OS and EFS curves tended to decline over time. Early lethal events were infections, whereas organ damage and secondary malignancies appeared afterwards, even a decade after HSCT. A non-myeloablative conditioning regimen appeared to be most advisable. Organ impairment present before HSCT seemed to favour the development of chronic graft-versus-host disease and T-B immune deficiency appeared to enhance pulmonary fibrosis. According to the present data, HSCT in DC is indicated in cases of progressive marrow failure, whereas in patients with pre-existing organ damage, this should be carefully evaluated. Further efforts to investigate treatment alternatives to HSCT should be encouraged.
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http://dx.doi.org/10.1111/bjh.15495DOI Listing
October 2018

Cytomegalovirus Serostatus Affects Autoreactive NK Cells and Outcomes of IL2-Based Immunotherapy in Acute Myeloid Leukemia.

Cancer Immunol Res 2018 09 6;6(9):1110-1119. Epub 2018 Jul 6.

TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.

Human cytomegalovirus (CMV) infection is reported to promote NK cell differentiation and education. The CMV-induced generation of highly differentiated adaptive-like NK cells has been proposed to affect favorably on the maintenance of remission in patients with acute myeloid leukemia (AML) after allogeneic stem cell transplantation (allo-SCT). The impact of CMV infection and adaptive-like NK cells on relapse and survival of patients with AML not receiving allo-SCT remains unknown. We assayed CMV IgG serostatus to determine past CMV infection in 81 nontransplanted AML patients who were receiving relapse-prevention immunotherapy comprising histamine dihydrochloride and low-dose interleukin-2 (HDC/IL2; NCT01347996). CMV seropositivity correlated negatively with leukemia-free and overall survival of patients receiving HDC/IL2, but did not correlate with outcomes in a contemporary control cohort. Analysis of outcome after stratification of patients based on concordant or discordant killer immunoglobulin-like receptor (KIR) and HLA genotypes implied that the negative impact of CMV seropositivity was restricted to patients lacking a ligand to inhibitory KIRs (iKIR). Previous CMV infection was also associated with fewer NK cells expressing only nonself iKIRs (NS-iKIR). We propose that CMV-driven NK cell education depletes the population of NS-iKIR NK cells, which in turn reduces the clinical benefit of relapse-preventive immunotherapy in AML. .
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http://dx.doi.org/10.1158/2326-6066.CIR-17-0711DOI Listing
September 2018

A prospective study of female genital chronic graft-versus-host disease symptoms, signs, diagnosis and treatment.

Acta Obstet Gynecol Scand 2018 Sep 5;97(9):1122-1129. Epub 2018 Jun 5.

Department of Obstetrics and Gynecology, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.

Introduction: Female genital chronic graft-versus-host disease (cGvHD) is a complication of allogeneic hematopoietic cell transplantation (alloHCT) for blood malignancies. Unattended inflammation and fibrosis in the vulva and vagina may lead to total vaginal stenosis. The course and treatment of genital cGvHD was observed in this population-based prospective study.

Material And Methods: Women (n = 41) receiving alloHCT in 2005-10 were examined before and at 3, 6, 9, 12, 18, 24, 30 and 36 months post-transplant. Vulvovaginal signs were documented, National Institutes of Health clinical scores were calculated, and women completed questionnaires on symptoms, the Female Sexual Distress Scale and the Beck Depression Inventory. Local immunosuppressive treatment was given weekly.

Results: Genital cGvHD was diagnosed in 27 women (incidence 56% at 12 months; 66% at 36 months); extragenital cGvHD was found in 21/27. The most common signs at diagnosis were red and white spots, reticular white lines, fissures, synechiae and telangiectasia; symptoms included dryness, itching, dyspareunia, pain or no symptoms. Thirteen women were treated on a schedule of tacrolimus and clobetazol ointments. Although some signs progressed during treatment, only two women developed total stenosis. At 36 months, 12 women still had genital cGvHD.

Conclusions: Genital cGvHD develops mainly in the first year after alloHCT. Early intervention may halt its progress to severe fibrosis, but despite correct diagnosis and treatment, symptoms and signs may become chronic. Women who develop genital cGvHD following alloHCT require life-long gynecological supervison and care.
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http://dx.doi.org/10.1111/aogs.13366DOI Listing
September 2018

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

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

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

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

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

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

A Modified Post-Transplant Cyclophosphamide Regimen, for Unmanipulated Haploidentical Marrow Transplantation, in Acute Myeloid Leukemia: A Multicenter Study.

Biol Blood Marrow Transplant 2018 06 5;24(6):1243-1249. Epub 2018 Feb 5.

Istituto di Ematologia, Policlinico Universitario A Gemelli, Università Cattolica, Roma, Italy. Electronic address:

We report a modified post-transplant cyclophosphamide (PT-CY) regimen, for unmanipulated haploidentical marrow transplants, in 150 patients with acute myeloid leukemia (AML). All patients received a myeloablative regimen, cyclosporine A (CsA) on day 0, mycophenolate on day +1, and PT-CY 50 mg/kg on days +3 and +5. The median age was 51 (range, 17-74) years, 51 (34%) patients had active disease at transplant, and the median follow-up of surviving patients 903 (range, 150-1955) days. The cumulative incidence (CI) of engraftment, acute graft-versus-host disease (GVHD) grade II to IV, and moderate/severe chronic GVHD was 92%, 17%, and 15%, respectively. The 4-year CI of transplant-related mortality (TRM) and relapse was 20% and 24%, respectively. Four-year survival for remission patients was 72% (74% versus 67% for <60 or ≥60 years of age) and 26% for advanced patients (17% versus 41% for <60 or ≥60 years of age). In a multivariate analysis, active disease at transplant was the only negative predictor of survival, TRM and relapse. The original PT-CY regimen can be modified with CsA on day 0, still providing protection against GVHD, low toxicity, and encouraging low relapse incidence in AML patients, also over 60 years of age.
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http://dx.doi.org/10.1016/j.bbmt.2018.01.031DOI Listing
June 2018

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

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

South Älvsborg Hospital Borås, Sweden.

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

Role of regulatory T cells in acute myeloid leukemia patients undergoing relapse-preventive immunotherapy.

Cancer Immunol Immunother 2017 Nov 18;66(11):1473-1484. Epub 2017 Jul 18.

TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Medicinaregatan 1F, Box 425, 413 90, Gothenburg, Sweden.

Regulatory T cells (T) have been proposed to dampen functions of anti-neoplastic immune cells and thus promote cancer progression. In a phase IV trial (Re:Mission Trial, NCT01347996, http://www.clinicaltrials.gov ) 84 patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received ten consecutive 3-week cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2) to prevent relapse of leukemia in the post-consolidation phase. This study aimed at defining the features, function and dynamics of Foxp3CD25CD4 T during immunotherapy and to determine the potential impact of T on relapse risk and survival. We observed a pronounced increase in T counts in peripheral blood during initial cycles of HDC/IL-2. The accumulating T resembled thymic-derived natural T (nT), showed augmented expression of CTLA-4 and suppressed the cell cycle proliferation of conventional T cells ex vivo. Relapse of AML was not prognosticated by T counts at onset of treatment or after the first cycle of immunotherapy. However, the magnitude of T induction was diminished in subsequent treatment cycles. Exploratory analyses implied that a reduced expansion of T in later treatment cycles and a short T telomere length were significantly associated with a favorable clinical outcome. Our results suggest that immunotherapy with HDC/IL-2 in AML entails induction of immunosuppressive T that may be targeted for improved anti-leukemic efficiency.
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http://dx.doi.org/10.1007/s00262-017-2040-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645432PMC
November 2017

NOX2-dependent immunosuppression in chronic myelomonocytic leukemia.

J Leukoc Biol 2017 08 14;102(2):459-466. Epub 2017 Mar 14.

TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden; and

Chronic myelomonocytic leukemia (CMML) is a myeloproliferative and myelodysplastic neoplasm with few treatment options and dismal prognosis. The role of natural killer (NK) cells and other antileukemic lymphocytes in CMML is largely unknown. We aimed to provide insight into the mechanisms of immune evasion in CMML with a focus on immunosuppressive reactive oxygen species (ROS) formed by the myeloid cell NADPH oxidase-2 (NOX2). The dominant population of primary human CMML cells was found to express membrane-bound NOX2 and to release ROS, which, in turn, triggered extensive PARP-1-dependent cell death in cocultured NK cells, CD8 T effector memory cells, and CD8 T effector cells. Inhibitors of ROS formation and scavengers of extracellular ROS prevented CMML cell-induced lymphocyte death and facilitated NK cell degranulation toward Ab-coated, primary CMML cells. In patients with CMML, elevation of immature cell counts (CD34) in blood was associated with reduced expression of several NK cell-activating receptors. We propose that CMML cells may use extracellular ROS as a targetable mechanism of immune escape.
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http://dx.doi.org/10.1189/jlb.5VMA1116-454RDOI Listing
August 2017

Role of natural killer cell subsets and natural cytotoxicity receptors for the outcome of immunotherapy in acute myeloid leukemia.

Oncoimmunology 2016;5(1):e1041701. Epub 2015 May 5.

TIMM Laboratory; Sahlgrenska Cancer Center; University of Gothenburg ; Gothenburg, Sweden.

In a phase IV trial, 84 patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose human recombinant interleukin 2 (IL-2) for 18 months to prevent leukemic relapse. During cycles, the treatment resulted in expansion of CD56(bright) (CD3(-)/16(-)/56(bright)) and CD16(+) (CD3(-)/16(+)/56(+)) natural killer (NK) cells in the blood along with increased NK cell expression of the natural cytotoxicity receptors (NCRs) NKp30 and NKp46. Multivariate analyses correcting for age and risk group demonstrated that high CD56(bright) NK cell counts and high expression of NKp30 or NKp46 on CD16(+) NK cells independently predicted leukemia-free survival (LFS) and overall survival (OS). Our results suggest that the dynamics of NK cell subsets and their NCR expression may determine the efficiency of relapse-preventive immunotherapy in AML.
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http://dx.doi.org/10.1080/2162402X.2015.1041701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760300PMC
May 2015

Dynamics of cytotoxic T cell subsets during immunotherapy predicts outcome in acute myeloid leukemia.

Oncotarget 2016 Feb;7(7):7586-96

TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.

Preventing relapse after chemotherapy remains a challenge in acute myeloid leukemia (AML). Eighty-four non-transplanted AML patients in first complete remission received relapse-preventive immunotherapy with histamine dihydrochloride and low-dose interleukin-2 in an international phase IV trial (ClinicalTrials.gov; NCT01347996). Blood samples were drawn during cycles of immunotherapy and analyzed for CD8+ (cytotoxic) T cell phenotypes in blood. During the first cycle of therapy, a re-distribution of cytotoxic T cells was observed comprising a reduction of T effector memory cells and a concomitant increase of T effector cells. The dynamics of T cell subtypes during immunotherapy prognosticated relapse and survival, in particular among older patients and remained significantly predictive of clinical outcome after correction for potential confounders. Presence of CD8+ T cells with specificity for leukemia-associated antigens identified patients with low relapse risk. Our results point to novel aspects of T cell-mediated immunosurveillance in AML and provide conceivable biomarkers in relapse-preventive immunotherapy.
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http://dx.doi.org/10.18632/oncotarget.7210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884940PMC
February 2016

NK cell expression of natural cytotoxicity receptors may determine relapse risk in older AML patients undergoing immunotherapy for remission maintenance.

Oncotarget 2015 Dec;6(40):42569-74

TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg 405 30, Sweden.

In a phase IV trial, eighty-four patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose human recombinant interleukin-2 (IL-2) to prevent relapse in the post-consolidation phase. Aspects of natural killer (NK) cell biology were analyzed before and during immunotherapy with focus on outcome in older patients. In younger (<60 years old, n = 37) and older patients (>60 years old, n = 47), treatment with HDC/IL-2 resulted in an expansion of CD56(bright) and CD16+ NK cells in blood along with an increased NK cell expression of the natural cytotoxicity receptors (NCR) NKp30 and NKp46. In older patients, a high expression of NKp30 or NKp46 on CD16+ NK cells before and during therapy predicted leukemia-free and overall survival. These results suggest that NK cell functions determine relapse risk and survival in older AML patients and point to biomarkers of efficacy in protocols for remission maintenance.
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http://dx.doi.org/10.18632/oncotarget.5559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767453PMC
December 2015

Genital chronic graft-versus-host disease in females: a cross-sectional study.

Biol Blood Marrow Transplant 2014 Jun 2;20(6):806-11. Epub 2014 Mar 2.

Section of Hematology and Coagulation, Sahlgrenska University Hospital, Sahlgrenska Academy, Göteborg, Sweden. Electronic address:

Using the National Institutes of Health (NIH) consensus criteria for chronic graft-versus-host disease (cGVHD), we assessed the prevalence, symptoms, and clinical signs of female genital cGVHD in a cross-sectional population-based study. Forty-two women were evaluated at a median of 80 months (range, 13 to 148 months) after undergoing hematopoietic stem cell transplantation (HSCT). Medical history, ongoing medications, and genital signs and symptoms were recorded. Gynecologic examination for the diagnosis and clinical scoring of genital cGVHD was combined with clinical scoring of extragenital cGVHD for the estimation of each patient's global cGVHD score. Biopsy specimens from the genital mucosa were obtained from 38 patients. Genital cGVHD was diagnosed in 22 of 42 patients (52%). Its presence was associated with systemic corticoid steroid treatment of extragenital cGVHD (P = .001), older age (P = .07), and HSCT from a sibling donor (P = .002). Five patients had isolated genital cGVHD. Dryness, pain, smarting pain (P < .05 for all), and dyspareunia (P = .001) were observed more frequently in the women with genital cGVHD. Twelve patients had advanced genital cGVHD (clinical score 3), which was the main factor explaining the high rate (15 of 42) of severe global cGVHD. The rate of genital cGVHD was similar (P = .37) in patients with a follow-up of ≥80 months (10 of 22) and those with a follow-up of <80 months (12 of 20). We found no convincing relationship between clinical diagnosis and histopathological assessment of mucosal biopsy specimens. In our group of women with a long follow-up after HSCT, genital cGVHD was common and in many cases incorrectly diagnosed. Genital cGVHD causes genital symptoms and affects sexual life, and may present without any other cGVHD, warranting early and continuous gynecologic surveillance in all women after HSCT.
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http://dx.doi.org/10.1016/j.bbmt.2014.02.016DOI Listing
June 2014

Tyrosine kinase inhibitor usage, treatment outcome, and prognostic scores in CML: report from the population-based Swedish CML registry.

Blood 2013 Aug 10;122(7):1284-92. Epub 2013 Jul 10.

Department of Medical Science and Division of Hematology, University Hospital, Uppsala, Sweden.

Clinical management guidelines on malignant disorders are generally based on data from clinical trials with selected patient cohorts. In Sweden, more than 95% of all patients diagnosed with chronic myeloid leukemia (CML) are reported to the national CML registry, providing unique possibilities to compile population-based information. This report is based on registry data from 2002 to 2010, when a total of 779 patients (425 men, 354 women; median age, 60 years) were diagnosed with CML (93% chronic, 5% accelerated, and 2% blastic phase) corresponding to an annual incidence of 0.9/100,000. In 2002, approximately half of the patients received a tyrosine kinase inhibitor as initial therapy, a proportion that increased to 94% for younger (<70 years) and 79% for older (>80 years) patients during 2007-2009. With a median follow-up of 61 months, the relative survival at 5 years was close to 1.0 for patients younger than 60 years and 0.9 for those aged 60 to 80 years, but only 0.6 for those older than 80 years. At 12 months, 3% had progressed to accelerated or blastic phase. Sokal, but not European Treatment and Outcome Study, high-risk scores were significantly linked to inferior overall and relative survival. Patients living in university vs nonuniversity catchment areas more often received tyrosine kinase inhibitors up front but showed comparable survival.
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http://dx.doi.org/10.1182/blood-2013-04-495598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744993PMC
August 2013

Human herpesvirus type 6 DNAemia and infection following allogeneic stem cell transplantation with a focus on long-term outcome.

Scand J Infect Dis 2013 Jul 5;45(7):557-61. Epub 2013 Mar 5.

Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Cases of human herpesvirus type 6 (HHV-6) infection and disease were retrospectively analysed in a cohort of 97 allogeneic haematopoietic stem cell transplantation (allo-SCT) patients in Gothenburg, Sweden (1997-2001). Altogether 54 of 97 (56%) patients were tested for HHV-6. HHV-6 DNAemia was detected in 15 of the tested patients at a median of 76 (range 24-387) days after SCT. Nine of these patients were treated against HHV-6 infection and disease for a total of 11 treatment episodes. The morbidity associated with HHV-6 DNAemia following allo-SCT was in most cases moderate. The overall 1-y survival among the patients with HHV-6 DNAemia was 11/15 (73%) and the 5-y survival was 10/15 (67%), which was not significantly different from the whole cohort.
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http://dx.doi.org/10.3109/00365548.2013.773069DOI Listing
July 2013

Chronic myeloid leukemic cells trigger poly(ADP-ribose) polymerase-dependent inactivation and cell death in lymphocytes.

J Leukoc Biol 2013 Jan 16;93(1):155-60. Epub 2012 Oct 16.

University of Gothenburg, Göteborg, Sweden.

NK cells and T cells are commonly dysfunctional in CML, and their status may determine the course of disease. We aimed to define the molecular mechanisms of leukemia-induced immunosuppression with focus on the role of ROS and the PARP-1 pathway of cell death. Malignant granulocytes from patients with BCR-ABL-positive CML expressed the oxygen radical-producing enzyme NOX, produced large amounts of ROS, and triggered extensive cell death in NK cells. Inhibition of PARP-1 maintained NK cell viability in cocultures with suppressive leukemic cells. Under conditions of oxidative stress, PARP-1 inhibition upheld the capacity of NK cells to kill myeloid leukemic cells, in addition to restoring the proliferation and cytokine production of NK cells and cytotoxic T cells. Our findings are suggestive of a novel pathway of relevance to immunosuppression in CML.
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http://dx.doi.org/10.1189/jlb.0512257DOI Listing
January 2013

Rapid salvage treatment with virus-specific T cells for therapy-resistant disease.

Clin Infect Dis 2012 Oct 17;55(8):1064-73. Epub 2012 Jul 17.

Therapeutic Immunology Unit, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.

Background: Viral infections are major complications after allogeneic hematopoietic stem cell transplantation (HSCT). During posttransplant immunosuppression the regular T-cell control is compromised. Even if treatment strategies against infections caused by herpes viruses such as cytomegalovirus, Epstein-Barr virus, and adenovirus have improved, the mortality rate is still considerable. If primary antiviral therapy fails or cannot be tolerated, adoptive therapy with virus-specific cytotoxic T cells (CTL) can be utilized.

Methods: In this study, we used virus-specific CTLs to treat 8 patients suffering from severe viral infections after allogeneic HSCT. Using positive selection with HLA multimers and magnetic beads, we isolated CTLs from both frozen donor material as well as third-party donors within hours.

Results: At 90 days after CTL infusions 7 out of 8 patients were still living. CTLs infused from third-party donors were detected in 5 of 6 patients up to 76 days after infusion. No graft-versus-host disease associated with CTL infusions was observed.

Conclusions: Our separation approach offers a rapid alternative for adoptive CTL therapy if primary antiviral treatment strategies fail. Because no prolonged expansion steps are needed, this method may be used for early treatment of patients suffering from life-threatening infectious complications.
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http://dx.doi.org/10.1093/cid/cis625DOI Listing
October 2012

Remission maintenance in acute myeloid leukemia: impact of functional histamine H2 receptors expressed by leukemic cells.

Haematologica 2012 Dec 11;97(12):1904-8. Epub 2012 Jun 11.

Department of Sahlgrenska Cancer Center, University of Gothenburg, Sweden.

Post-consolidation immunotherapy with histamine dihydrochloride and interleukin-2 has been shown to improve leukemia-free survival in acute myeloid leukemia in a phase III trial. For this study, treatment efficacy was determined among 145 trial patients with morphological forms of acute myeloid leukemia as defined by the French-American-British classification. Leukemia-free survival was strongly improved in M4/M5 (myelomonocytic/monocytic) leukemia but not in M2 (myeloblastic) leukemia. We also analyzed histamine H(2) receptor expression by leukemic cells recovered from 26 newly diagnosed patients. H(2) receptors were typically absent from M2 cells but frequently expressed by M4/M5 cells. M4/M5 cells, but not M2 cells, produced reactive oxygen species that triggered apoptosis in adjacent natural killer cells. These events were significantly inhibited by histamine dihydrochloride. Our data demonstrate the presence of functional histamine H(2) receptors on human AML cells and suggest that expression of these receptors by leukemic cells may impact on the effectiveness of histamine-based immunotherapy.
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http://dx.doi.org/10.3324/haematol.2012.066399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3590096PMC
December 2012

Monocytic AML cells inactivate antileukemic lymphocytes: role of NADPH oxidase/gp91(phox) expression and the PARP-1/PAR pathway of apoptosis.

Blood 2012 Jun 1;119(24):5832-7. Epub 2012 May 1.

Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.

Dysfunction of T cells and natural killer (NK) cells has been proposed to determine the course of disease in acute myeloid leukemia (AML), but only limited information is available on the mechanisms of lymphocyte inhibition. We aimed to evaluate to what extent human malignant AML cells use NADPH oxidase-derived reactive oxygen species (ROS) as an immune evasion strategy. We report that a subset of malignant myelomonocytic and monocytic AML cells (French-American-British [FAB] classes M4 and M5, respectively), recovered from blood or BM of untreated AML patients at diagnosis, expressed the NADPH oxidase component gp91(phox). Highly purified FAB M4/M5 AML cells produced large amounts of ROS on activation and triggered poly-[ADP-ribose] polymerase-1-dependent apoptosis in adjacent NK cells, CD4(+) T cells, and CD8(+) T cells. In contrast, immature (FAB class M1) and myeloblastic (FAB class M2) AML cells rarely expressed gp91(phox), did not produce ROS, and did not trigger NK or T-cell apoptosis. Microarray data from 207 AML patients confirmed a greater expression of gp91(phox) mRNA by FAB-M4/M5 AML cells than FAB-M1 cells (P < 10(-11)) or FAB-M2 cells (P < 10(-9)). Our data are suggestive of a novel mechanism by which monocytic AML cells evade cell-mediated immunity.
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http://dx.doi.org/10.1182/blood-2011-11-391722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418695PMC
June 2012

High-dose therapy and autologous stem cell transplantation in first relapse for diffuse large B cell lymphoma in the rituximab era: an analysis based on data from the European Blood and Marrow Transplantation Registry.

Biol Blood Marrow Transplant 2012 May 17;18(5):788-93. Epub 2011 Oct 17.

CHU de l'Archet, Nice, France.

Autologous stem cell transplantation (ASCT) consolidation remains the treatment of choice for patients with relapsed diffuse large B cell lymphoma. The impact of rituximab combined with chemotherapy in either first- or second-line therapy on the ultimate results of ASCT remains to be determined, however. This study was designed to evaluate the benefit of ASCT in patients achieving a second complete remission after salvage chemotherapy by retrospectively comparing the disease-free survival (DFS) after ASCT for each patient with the duration of the first complete remission (CR1). Between 1990 and 2005, a total of 470 patients who had undergone ASCT and reported to the European Blood and Bone Transplantation Registry with Medical Essential Data Form B information were evaluated. Of these 470 patients, 351 (74%) had not received rituximab before ASCT, and 119 (25%) had received rituximab before ASCT. The median duration of CR1 was 11 months. The median time from diagnosis to ASCT was 24 months. The BEAM protocol was the most frequently used conditioning regimen (67%). After ASCT, the 5-year overall survival was 63% (95% confidence interval, 58%-67%) and 5-year DFS was 48% (95% confidence interval, 43%-53%) for the entire patient population. Statistical analysis showed a significant increase in DFS after ASCT compared with duration of CR1 (median, 51 months versus 11 months; P < .001). This difference was also highly significant for patients with previous exposure to rituximab (median, 10 months versus not reached; P < .001) and for patients who had experienced relapse before 1 year (median, 6 months versus 47 months; P < .001). Our data indicate that ASCT can significantly increase DFS compared with the duration of CR1 in relapsed diffuse large B cell lymphoma and can alter the disease course even in patients with high-risk disease previously treated with rituximab.
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http://dx.doi.org/10.1016/j.bbmt.2011.10.010DOI Listing
May 2012