To Örebro University

Patients with high-risk myelodysplastic syndromes (MDS) with a chromosome 5q deletion (del(5q)) have a poor prognosis and are often associated with a complex karyotype and TP53 mutations, factors worsening the prognosis. The hypomethylating agent azacitidine (AZA) is the first-line treatment. Lenalido-mide (LEN) is an effective therapy for lower-risk MDS with del(5q).

The aim of this thesis were clinical and genetic studies in patients with high-risk MDS and acute myeloid leukemia (AML) with 20-30% marrow blasts with a karyotype including del(5q). In a prospective, multicenter, open-label, ran-domized phase II study, we studied if AZA + LEN was superior to AZA alone in high-risk MDS and AML with 20-30% marrow blasts with del(5q). Seventy-two patients were included between 2012 and 2017. The overall response rate (ORR) in the treated cohort was 39% for AZA and 44% for AZA + LEN (P=0.63). The addition of LEN to AZA did not improve outcome. In paper II we studied the influence of cytogenetics on treatment response in the study and if specific cytogenetic findings could predict outcome. Patients with del(5q) and complex karyotype or an unbalanced translocation of 5q had a shorter median overall survival (OS) (P=0.004). The aim in paper III was to op-timize diagnostic procedures and follow-up assessment with cytomorphology, bone marrow trephine biopsy and immunohistochemistry (IHC) in patients with higher-risk MDS and AML with 20-30% blasts with a karyotype including del(5q). In 18 patients (25%) a higher bone marrow blast percentage was de-tected by IHC compared to cytomorphology, shifting the diagnosis to either a higher-risk MDS subgroup or AML and is useful for correct subclassification in del(5q) high-risk myeloid disease and for response assessment.

In conclusion, the findings in this thesis show that high-risk MDS with del(5q) is a myeloid disorder with a dismal prognosis. There seems to be a window of molecular response to AZA after 3 months of treatment. Future studies should focus on the therapeutic window as a possibility for allogeneic stem cell trans-plantation.

In myelodysplastic syndromes (MDS), cytogenetic characteristics of the malignant bone marrow cells influence the clinical course. The aim of this study was to evaluate whether cytogenetics is useful to predict outcome and response in patients with del(5q) under azacitidine (AZA) ± lenalidomide (LEN) therapy. We therefore performed comprehensive cytogenetic analyses in MDS patients with del(5q) treated within the randomized phase II trial NMDSG10B. Seventy-two patients were enrolled in the study and 46 patients (64%) had sufficient cytogenetics at inclusion and response evaluation. Karyotyping was significantly more sensitive during follow-up to detect del(5q) compared to FISH, 34 patients (97%) versus 27 patients (77%) (p = 0.027). The overall response rate (ORR) did not differ between the 11 patients with < 3 aberrations (median 1 aberration) and the 59 patients with ≥ 3 aberrations (median 7 aberrations, range 3-16), while ≥ 3 aberrations were associated with shorter overall survival (OS), 9.9 months versus 25.2 months (p = 0.004). OS was significantly shorter in patients with unbalanced translocation of 5q than patients with del (5)(q14q34), 8.4 months versus 21.1 months (p = 0.004). Both complex karyotype and multi-hit TP53 alterations were more frequent in patients with unbalanced translocations of 5q versus del (5)(q14q34), 98% and 88% versus 67% and 47% (each p = < 0.001). Most patients with cytogenetic progression had multi-hit TP53 alterations at inclusion. Cytogenetic progression occurred at a similar frequency in the AZA arm and in the AZA + LEN arm. In summary, this study in homogenously treated MDS patients with different abnormalities of 5q demonstrates the influence of cytogenetics on treatment results. Trial Registration: EudraCT number: 2011-001639-21; ClinicalTrials.gov identifier: NCT01556477.

PURPOSE: Clinical relapse is the major threat for patients with myelodysplastic syndrome (MDS) undergoing hematopoietic stem-cell transplantation (HSCT). Early detection of measurable residual disease (MRD) would enable preemptive treatment and potentially reduced relapse risk.

METHODS: Patients with MDS planned for HSCT were enrolled in a prospective, observational study evaluating the association between MRD and clinical outcome. We collected bone marrow (BM) and peripheral blood samples until relapse, death, or end of study 24 months after HSCT. Patient-specific mutations were identified with targeted next-generation sequencing (NGS) panel and traced using droplet digital polymerase chain reaction (ddPCR).

RESULTS: Of 266 included patients, estimated relapse-free survival (RFS) and overall survival (OS) rates 3 years after HSCT were 59% and 64%, respectively. MRD results were available for 221 patients. Relapse was preceded by positive BM MRD in 42/44 relapses with complete MRD data, by a median of 71 (23-283) days. Of 137 patients in continuous complete remission, 93 were consistently MRD-negative, 39 reverted from MRD+ to MRD-, and five were MRD+ at last sampling. Estimated 1 year-RFS after first positive MRD was 49%, 39%, and 30%, using cutoff levels of 0.1%, 0.3%, and 0.5%, respectively. In a multivariate Cox model, MRD (hazard ratio [HR], 7.99), WHO subgroup AML (HR, 4.87), TP53 multi-hit (HR, 2.38), NRAS (HR, 3.55), and acute GVHD grade III-IV (HR, 4.13) were associated with shorter RFS. MRD+ was also independently associated with shorter OS (HR, 2.65). In a subgroup analysis of 100 MRD+ patients, presence of chronic GVHD was associated with longer RFS (HR, 0.32).

CONCLUSION: Assessment of individualized MRD using NGS + ddPCR is feasible and can be used for early detection of relapse. Positive MRD is associated with shorter RFS and OS (ClinicalTrials.gov identifier: NCT02872662).

Comorbidities influence the mortality in patients with myelodysplastic syndromes, and a growing body of evidence suggest that comorbidity history should be used in addition to established prognostic indices. A comorbidity index specific for MDS, the MDS-CI, was introduced a decade ago. In this study we aim to construct an MDS-CI version based on diagnoses from register data only, to expand its use beyond the clinical setting to retrospective and register based studies. We further test this version on a Swedish population-based MDS cohort of 2947 patients, and compare its prognostic accuracy to that of Charlson Comorbidity Index. Our register based MDS-CI divided patients into three risk groups of similar proportions as have been published for the original MDS-CI. Compared to low risk patients, intermediate and high risk patients had 50 % and 70 % higher mortality, respectively. The prognostic value of MDS-CI was equal to that of Charlson comorbidity index. Adding MDS-CI to the established prognostic factors IPSS-R and age increased the prognostic accuracy. In summary, we demonstrate that MDS-CI can be adequately estimated from diagnoses recorded in registers only, and that it is a useful tool in any future study on myelodysplastic syndromes with a need to adjust for comorbidities.

In this population-based study, we aimed to characterize and compare subgroups of therapy-related Myelodysplastic syndromes (t-MDS) and define the implications of type of previous treatment and primary disease. We combined data from MDS patients, diagnosed between 2009 and 2017 (n = 2705), in the nationwide Swedish MDS register, with several health registers. Furthermore, using matched population controls, we investigated the prevalence of antecedent malignancies in MDS patients in comparison with the general population. This first ever nationwide study on t-MDS confirms a shorter median survival for t-MDS compared to de novo MDS (15.8 months vs 31.1 months, p < 0.001). T-MDS patients previously treated with radiation only had disease characteristics with a striking resemblance to de novo-MDS, in sharp contrast to patients treated with chemotherapy who had a significantly higher risk profile. IPSS-R and the WHO classification differentiated t-MDS into different risk groups. As compared with controls, MDS patients had a six-fold increased prevalence of a previous hematological malignancy but only a 34% increased prevalence of a previous solid tumor. T-MDS patients with a previous hematological malignancy had a dismal prognosis, due both to mortality related to their primary disease and to high-risk MDS.

Objectives: To assess whether socioeconomic indices such as income and educational level can explain part of the variation in survival among patients with myelodysplastic syndromes, and further to assess whether these factors influence care and treatment decisions.

Methods: Population-based cohort study on 2945 Swedish patients diagnosed between 2009 and 2018 and included in the Swedish MDS Register. Relative mortality was assessed by Cox regression, whereas treatment differences were assessed by Poisson regression. Regarding mortality, patients were also compared to a matched comparison group from the general population.

Results: Mortality was 50% higher among patients in the lowest income category compared to the highest and 40% higher in patients with mandatory school education only compared to those with college or university education. Treatment with hypomethylating agents and allogeneic stem cell transplantation, as well as investigation with cytogenetic diagnostics were also linked to income and education. The findings were not explained by differences in risk class or comorbidity at the time of diagnosis.

Conclusions: Income and education are linked to survival among patients with myelodysplastic syndromes. Socioeconomic status also seems to influence treatment intensity as patients with less income and education to a lesser degree receive hypomethylating agents and transplants.

Outcomes in chronic myelomonocytic leukaemia (CMML) are highly variable and may be affected by comorbidity. Therefore, prognostic models and comorbidity indices are important tools to estimate survival and to guide clinicians in individualising treatment. In this nationwide population-based study, we assess comorbidities and for the first time validate comorbidity indices in CMML. We also compare the prognostic power of: the revised International Prognostic Scoring System (IPSS-R), CMML-specific prognostic scoring system (CPSS), MD Anderson Prognostic Scoring System (MDAPS) and Mayo score. In this cohort of 337 patients with CMML, diagnosed between 2009 and 2015, the median overall survival was 21 center dot 3 months. Autoimmune conditions were present in 25% of the patients, with polymyalgia rheumatica and Hashimoto's thyroiditis being most common. Of the tested comorbidity indices: the Charlson Comorbidity Index (CCI), Haematopoietic cell transplantation-specific Comorbidity Index (HCT-CI) and Myelodysplastic Syndrome-Specific Comorbidity Index (MDS-CI), CCI had the highest C-index (0 center dot 62) and was the only comorbidity index independently associated with survival in multivariable analyses. When comparing the prognostic power of the scoring systems, the CPSS had the highest C-index (0 center dot 69). In conclusion, using 'real-world' data we found that the CCI and CPSS have the best prognostic power and that autoimmune conditions are overrepresented in CMML.