Martin Höglund

Uppsala University | UU · Department of Medical Sciences

The aim of this prospective, international multicenter, pseudorandomized study using the donor versus no-donor concept to compare RICT HCT to standard-of-care chemotherapy in intermediate- or high risk AML patients 50 – 70 years in CR1. Part 1 included only patients with potential family donors (RD) at the date of HLA-typing of the first potential...

A comprehensive characterization of blood proteome profiles in cancer patients can contribute to a better understanding of the disease etiology, resulting in earlier diagnosis, risk stratification and better monitoring of the different cancer subtypes. Here, we describe the use of next generation protein profiling to explore the proteome signature...

Despite improvement of current treatment strategies and novel targeted drugs, relapse and treatment resistance largely determine the outcome for acute myeloid leukemia (AML) patients. To identify the underlying molecular characteristics, numerous studies have been aimed to decipher the genomic- and transcriptomic landscape of AML. Nevertheless, fur...

Cancer mortality is exacerbated by late-stage diagnosis. Liquid biopsies based on genomic biomarkers can noninvasively diagnose cancers. However, validation studies have reported ~10% sensitivity to detect stage I cancer in a screening population and specific types, such as brain or genitourinary tumors, remain undetectable. We investigated urine a...

In chronic myeloid leukemia (CML), combination therapies with tyrosine kinase inhibitors (TKIs) aim to improve the achievement of deep molecular remission that would allow therapy discontinuation. IFN-α is one promising candidate, as it has long-lasting effects on both malignant and immune cells. In connection with a multicenter clinical trial comb...

Studies of therapy-related AML (t-AML) are usually performed in selected cohorts and reliable incidence rates are lacking. In this study, we characterized, defined the incidence over time and studied prognostic implications in all t-AML patients diagnosed in Sweden between 1997 and 2015. Data were retrieved from nationwide population-based registri...

Background Treatment of newly diagnosed acute myeloid leukaemia (AML) is based on combination chemotherapy with cytarabine and anthracyclines. Five-year overall survival is below 30%, which has partly been attributed to cytarabine resistance. Preclinical data suggest that the addition of hydroxyurea potentiates cytarabine efficacy by increasing ara...

Background: Treatment of newly diagnosed acute myeloid leukaemia (AML) is based on combination chemotherapy with cytarabine and anthracyclines. Five-year overall survival is below 30%, which has partly been attributed to cytarabine resistance. Preclinical data suggest that addition of hydroxyurea potentiates cytarabine efficacy by increasing ara-CT...

Background Whole-genome sequencing (WGS) and whole-transcriptome sequencing (WTS), with the ability to provide comprehensive genomic information, have become the focal point of research interest as novel techniques that can support precision diagnostics in routine clinical care of patients with various cancer types, including hematological malignan...

With increasingly effective treatments, early death (ED) has become the dominant reason for therapeutic failure in patients with acute promyelocytic leukemia (APL). To better prevent ED, patients with high-risk of ED must be identified. Our aim was to develop a score that predicts the risk of ED in a real-life setting. We used APL patients in the p...

Tyrosine kinase inhibitors (TKIs) have profoundly improved the clinical outcome for patients with chronic myeloid leukemia (CML), but their overall survival is still subnormal and the treatment is associated with adverse events. In a large cohort‐study, we assessed the morbidity in 1328 Swedish CML chronic phase patients diagnosed 2002–2017 and tre...

National and regional population-based registries are, provided diagnostic accuracy and full coverage of the target population, indispensable tools for epidemiological research. CML registries with a more comprehensive reporting may also provide complementary data on treatment outcome to those obtained from clinical trials. Reports from several Eur...

Acute myeloid leukemia (AML) is associated with a high economic and clinical burden. Recently novel therapies have been added to standard treatment regimens. Here, we evaluated the economic impact of AML up until the introduction of these novel therapies. Individual data on 2954 adult patients diagnosed from 2007 to 2015 from five Swedish national...

Clinical trials show that tyrosine kinase inhibitor (TKI) treatment can be discontinued in selected patients with chronic myeloid leukaemia (CML). Although updated CML guidelines support such procedure in clinical routine, data on TKI stopping outside clinical trials are limited. In this retrospective study utilising the Swedish CML registry, we ex...

The Swedish national guidelines for treatment of acute myeloid leukemia (AML) recommend analysis of measurable residual disease (MRD) by multiparameter flow cytometry (MFC) in bone marrow in the routine clinical setting. The Swedish AML registry contains such MRD data in AML patients diagnosed 2011–2019. Of 327 patients with AML (non-APL) with MRD-...

Acute myeloid leukemia (AML) with t(9;22)(q34;q11), also known as AML with BCR‐ABL1, is a rare, provisional entity in the WHO 2016 classification and is considered a high‐risk disease according to the European LeukemiaNet 2017 risk stratification. We here present a retrospective, population‐based study of this disease entity from the Swedish Acute...

Introduction Large efforts have been made to divide bladder cancer into prognostic or predictive subtypes by unsupervised or semi-supervised clustering of mRNA data. To validate and make use of subtypes, classifiers must be constructed that accurately predicts subtypes in new samples. Variations of nearest centroid classification is commonly used,...

Introduction To describe the genetic relationship between the primary and recurrent bladder tumors and to identify their origins, different models such as the field cancerization, seeding, and intraepithelial migration have been proposed. The aim of this study was to investigate the genetic relationship in syn- and metachronous bladder tumors using...

Introduction Several groups, including ours, have identified STAG2 as a new bladder tumor suppressor gene. STAG2 is part of cohesin, a complex involved in chromosome segregation, DNA repair and chromatin organization. A role for STAG2 in hematopoietic stem cell self-renewal and differentiation has been shown. The mechanisms through which STAG2 cont...

Background Rituximab is widely used in the treatment of haematological malignancies, including chronic lymphoid leukaemia (CLL), the most common leukaemia in adults. However, some patients, especially those with high tumour burden, develop cytokine release syndrome (CRS). It is likely that more patients will develop therapy-linked CRS in the future...

Individuals suffering from cancer, including hematological malignancies, are at increased risk of cardiovascular disease (CVD). Elevated levels of several biomarkers in blood are associated with an increased risk of CVD. The aim of this study was to investigate whether a subset of such CVD risk biomarkers was elevated in patients with untreated chr...

Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recom...

In acute myeloid leukemia (AML) FLT3 internal tandem duplication (ITD) and nucleophosmin 1 (NPM1) mutations provide prognostic information with clinical relevance through choice of treatment, but the effect of age and sex on these molecular markers has not been evaluated. The Swedish AML Registry contains data on FLT3-ITD and NPM1 mutations dating...

Objectives The use of patient‐reported outcome (PRO) measured outside clinical trials is not well defined. We report the first analysis of the prospective PRO study within the Swedish acute myeloid leukemia (AML) and the acute lymphoblastic leukemia (ALL) registries. Methods PRO was requested 6 months after diagnosis. The EORTC Quality of life Que...

Introduction: AML affects all ages with an incidence rate of 5 per 100,000, but is much more frequent in older population. The overall lifetime risk of AML is estimated to be 0.5-1%. Long-term overall survival in younger (age < 60 years) is about 50%, but much worse among older population. Although AML therapy is one of the most resource-intensive...

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...

Background: Based on a previous report of increased chronic myeloid leukaemia (CML) risk following peptic ulcer, we hypothesised that chronic Helicobacter pylori infection could serve as a risk factor for CML. Methods: In a population-based, retrospective case-control study we used Swedish registry data on 980 CML patients and 4 960 age- and sex...

Purpose: Nucleophosmin 1 (NPM1) mutations are associated with a favorable prognosis in acute myeloid leukemia (AML) when an internal tandem duplication (ITD) in the fms-related tyrosine kinase 3 gene (FLT3) is absent (FLT3-ITDneg) or present with a low allelic ratio (FLT3-ITDlow). The 2017 European LeukemiaNet guidelines assume this is true regard...

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...

Background For AML (excluding APL), there has until recently been no major changes in AML‐specific drug therapy, but improvements of supportive care and access to allogeneic transplantation (SCT). Aims We aimed to analyze changes in survival from AML (non‐APL) over the period 1997–2016, and to identify and characterize patient subsets with greater...

Background AML affects all ages with an incidence rate of 5 per 100,000, but is much more frequent in older people. The overall lifetime risk of AML is estimated to be 0.5–1%. Long‐term overall survival in younger (age< 60 years) is about 50%, but much worse among older. Although AML therapy is one of the most resource‐intensive cancer treatments,...

Background and study design. Reduced intensity conditioning transplantation (RICT) is a commonly applied treatment option for AML patients >50 years of age. Prospective, controlled studies comparing RICT with standard chemotherapy are warranted. In this study, we aimed to prevent selection biases. Thus, patients were included prior to HLA typing of...

Purpose: CAR T cell therapy has been effective for patients with CD19+ B cell malignancies. Most studies have investigated second generation CARs with either CD28 or 4-1BB co-stimulatory domains in the CAR receptor. Here we describe the first clinical phase I/IIa trial using third generation CAR T cells targeting CD19 to evaluate safety and effica...

Introduction To describe the origin and the genetic relationship between primary bladder tumours and their recurrences, different models were proposed, such as, field cancerization, seeding, and intraepithelial migration. This study aims to investigate the genetic relationship in syn- and metachronous bladder tumours using different types of data,...

We previously reported that the anti-malarial drug quinacrine has potential to be repositioned for treatment of acute myeloid leukemia (AML). As a next step towards clinical use, we assessed the efficacy of quinacrine in an AML-PS mouse model and investigated possible synergistic effects when combining quinacrine with nine other antileukemic compou...

Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 201...

Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.

Leukemia accepted article preview online, 24 February 2017. doi:10.1038/leu.2017.71.

Objectives and methods: To ascertain the incidence/clinical implications of isolated autosomal trisomies in adult acute myeloid leukemia (AML), all such cases were retrieved from the Swedish AML Registry RESULTS: Of the 3,179 cytogenetically informative AMLs diagnosed January 1997 - May 2015, 246 (7.7%) had isolated trisomies. The frequency increa...

The novel aminopeptidase potentiated alkylating agent melflufen, was evaluated for activity in acute myeloid leukemia in a range of in vitro models, as well as in a patient derived xenograft study. All tested AML cell lines were highly sensitive to melflufen while melphalan was considerably less potent. In the HL-60 cell line model, synergy was obs...

Background: The etiology of chronic myeloid leukemia (CML) is essentially unknown with high doses of ionizing radiation being the only well established risk factor. We have recently published two large population-based studies showing an increased prevalence of other malignancies prior, as well as subsequent to a diagnosis of CML (Gunnarsson et al,...

Background: In chronic myeloid leukemia (CML) the combination treatment of tyrosine kinase inhibitors (TKIs) with interferon-α (IFN-α) has proved to be effective and well-tolerated. IFN-α has long-term immunomodulatory effects, and when combined to TKI therapy, it may increase the success rates for treatment free remission. In our recent clinical t...

Purpose: To evaluate the influence of socioeconomic variables on treatment selection and survival of patients with chronic myeloid leukaemia (CML). Methods: Using information available in population-based Swedish registries we evaluated indices of health, education and economy from the 980 patients in the Swedish CML register diagnosed between 2...

Recent studies suggest that a proportion of chronic myeloid leukemia (CML) patients in deep molecular remission can discontinue the tyrosine kinase inhibitor (TKI) treatment without disease relapse. In this multi-center, prospective clinical trial (EURO-SKI, NCT01596114) we analyzed the function and phenotype of T and NK cells and their relation to...

Poster presentation from the 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer.

Leukemia accepted article preview online, 31 October 2016. doi:10.1038/leu.2016.312.

Background: Patients treated for hematological malignancies have an increased risk of serious infections. Diagnosis and prompt initiation of therapy are essential. Bronchoalveolar lavage (BAL) is a well-established investigation for identifying the cause of pulmonary infiltrates in immunocompromised patients. The aim of the study was to determine t...

The EUTOS population-based registry includes data of all adult patients newly diagnosed with Ph+ and/or BCR-ABL1+ CML in 20 predefined countries and regions of Europe. Registration time ranged from 12 to 60 months between January 2008 and December 2013. Median age was 55 years and median observation time 29 months. 80% of patients were treated firs...

National and regional population-based registries are, provided diagnostic accuracy and full coverage of the target population, indispensible tools for epidemiological research. CML registries with a more comprehensive reporting may also provide complementary data on treatment outcome to those obtained from clinical trials. Reports from several Eur...

Inhibitors of BCL-2 such as venetoclax (ABT-199) and navitoclax (ABT-263) are clinically explored in several cancer types, including acute myeloid leukemia (AML), to selectively induce apoptosis in cancer cells. To identify robust biomarkers for BCL-2 inhibitor sensitivity, we evaluated the ex vivo sensitivity of fresh leukemic cells from 73 diagno...

Cytogenetic lesions often alter kinase signaling in acute myeloid leukemia (AML) and the addition of kinase inhibitors to the treatment arsenal is of interest. We have screened a kinase inhibitor library and performed combination testing to find promising drug-combinations for synergistic killing of AML cells. Cytotoxicity of 160 compounds in the l...

Objectives: The primary goal in management of chronic phase (CP) CML is to prevent disease progression to accelerated phase (AP) or blast crisis (BC). We have evaluated progression rates in a decentralised health care setting and characterised patients progressing to AP/BC on TKI treatment. Methods: Using data from the Swedish CML register, we i...

Purpose: A dramatic improvement in the survival of patients with chronic myeloid leukemia (CML) occurred after the introduction of imatinib mesylate, the first tyrosine kinase inhibitor (TKI). We assessed how these changes affected the life expectancy of patients with CML and life-years lost as a result of CML between 1973 and 2013 in Sweden. Mat...

Background: Tyrosine kinase inhibitors (TKIs) have increased survival dramatically for patients with chronic myeloid leukemia (CML), but continuous administration of these drugs may elicit long-term toxicity. Objective: To investigate the incidence of vascular events in patients with CML treated with first- and second-generation TKIs. Design:...

Dasatinib (DAS) and interferon-α have antileukemic and immunostimulatory effects and induce deep responses in chronic myeloid leukemia (CML). We assigned 40 newly diagnosed chronic phase CML patients to receive DAS 100 mg OD followed by addition of pegylated interferon-α2b (PegIFN) after three months (M3). The starting dose of PegIFN was 15 μg/week...

We recently reported an increased incidence of second malignancies in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKI). To elucidate whether this increase may be linked, not to TKI but rather to a hereditary or acquired susceptibility to develop cancer, we estimated the prevalence of malignancies, autoimmune dis...

The clinical outcome for patients with chronic myeloid leukemia (CML) has improved dramatically following the introduction of tyrosine kinase inhibitors. An improved survival, combined with a constant incidence, is expected to increase the prevalence of CML. However, data on the prevalence of CML remain scarce. We examined the overall and relative...

Key Points Whole-exome sequencing of CLL patients who relapsed after FCR treatment revealed frequent mutations in RPS15. RPS15 mutations are likely to be early clonal events and confer poor prognosis.

Purpose The rates of early mortality (EM) are high in patients receiving intensive chemotherapy for acute myeloid leukemia (AML). Decreasing EM-rates over time have recently been reported. The reason for the improvement is however elusive and generally attributed to better supportive antibiotic and antifungal treatment. We wanted to investigate th...

The prevalence of survivors of adult AML has previously been calculated, but the prevalent population has not been characterized. We analysed all 6289 patients diagnosed with adult AML from 1997-2013 as reported in the Swedish AML registry, with a complete survival follow-up. We found 1148 patients, 563 males and 585 females, who were alive on Janu...

Background: Tyrosine kinase inhibitors (TKIs) have significantly improved the treatment of CML. Even though TKI treatment is generally not considered curative, recent studies have shown that nearly half of CML patients who have achieve good and durable responses are able to stop the TKI treatment. However, patients who have successfully discontinue...

Purpose The rates of early mortality (EM) are high in patients receiving intensive chemotherapy for acute myeloid leukemia (AML). Decreasing EM-rates over time have recently been reported. The reason for the improvement is however elusive and generally attributed to better supportive antibiotic and antifungal treatment. We wanted to investigate thi...

Background Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-1.5 cases per 100,000 adults, accounting for ∼ 15-20 % of newly diagnosed patients with myeloid leukemia in adults. Treatment for CML has changed dramatically with the introduction of imatinib mesylate (IM), the first tyrosine kinase inhibitor (TKI) ta...

The prevalence of survivors of adult AML has previously been calculated, but the prevalent population has not been characterized. We analysed all 6289 patients diagnosed with adult AML from 1997-2013 as reported in the Swedish AML registry, with a complete survival follow-up. We found 1148 patients, 563 males and 585 females, who were alive on Janu...

Telomerase reverse transcriptase gene (TERT) promoter mutations are identified in many malignancies but not in hematological malignancies. Here we analyzed TERT and protection of telomeres 1 gene (POT1) mutations, and four different TERT SNPs in 256 acute myeloid leukemia (AML) patients. A significant association for increased risk of AML was found...

Telomerase reverse transcriptase gene (TERT) promoter mutations are identified in many malignancies but not in hematological malignancies. Here we analyzed TERT and protection of telomeres 1 gene (POT1) mutations, and four different TERT SNVs in 226 acute myeloid leukemia (AML) patients and 806 healthy individuals in a case referent design, where a...

Purpose To ascertain the clinical implications of high hyperdiploid (HH; 49-65 chromosomes) and tri-/tetraploid (TT; >65 chromosomes) adult acute myeloid leukemia (AML), all such cases were retrieved from the Swedish AML Registry. Results Of the 3,654 cytogenetically informative cases diagnosed between January 1997 and May 2014, 68 (1.9%) were HH (...

To find drugs suitable for repositioning for use against leukemia, samples from patients with chronic lymphocytic, acute myeloid and lymphocytic leukemias as well as peripheral blood mononuclear cells (PBMC) were tested in response to 1266 compounds from the LOPAC1280 library (Sigma). Twenty-five compounds were defined as hits with activity in all...

National and regional population-based registries are, provided diagnostic accuracy and full coverage of the target population, indispensible tools for epidemiological research. Chronic myeloid leukaemia (CML) registries with more comprehensive reporting may also provide complementary data on treatment outcome to those obtained from clinical trials...

Immune escape mechanisms promote tumor progression and are hurdles of cancer immunotherapy. Removing immunosuppressive cells before treatment can enhance efficacy. Tyrosine kinase inhibitors may be of interest to combine with immunotherapy since it has been shown that the inhibitor sunitinib reduces myeloid suppressor cells in patients with renal c...

Given that tyrosine kinase inhibitors (TKIs) have dramatically improved the survival of patients with chronic myeloid leukaemia (CML), we were interested in examining the possible risk of long-term adverse events, such as the emergence of other neoplasms. Therefore, we studied the development of second malignancies in 868 patients diagnosed with CM...

Previous studies have shown that patients with granulomatosis with polyangiitis (GPA) have an increased risk of hematological malignancies, especially leukemia. Our aim was to assess clinical characteristics and treatment of patients with GPA complicated by hematological malignancies with focus on leukemia and to describe these malignancies in more...

Despite improved diagnostics and better understanding of AML biology, the basic chemotherapy has remained unchanged for decades, with no progress in outcome. In Sweden, national guidelines for the comprehensive management of AML were implemented in 2006, containing primary therapy with daunorubicin 60 mg/sqm/8h d.1-3 and ara-C 1 g/sqm/2h b.i.d. d.1...

Background: Since continuous treatment with tyrosine kinase inhibitors (TKIs) has dramatically improved the survival of patients with chronic myeloid leukemia (CML), it is of interest to examine the possible risk of long-term adverse events. Previous studies have presented conflicting results regarding risk of second malignancies. Our aim was to ex...

Background: Recent reports suggest that approximately 40% of CML patients who have achieved sustained complete molecular remission are able to stop TKI treatment without disease relapse. However, there are no predictive markers for successful therapy discontinuation. Therefore, we set up an immunological sub-study in the ongoing pan-European EURO-S...