PURPOSE:In a multicenter prospective cohort study, we assessed the diagnostic yield of the Nordic guidelines for germline investigation in myeloid neoplasms and mapped the spectrum of inherited and somatic variants. EXPERIMENTAL DESIGN:Eighty-five patients (acute myeloid leukemia, n = 38; myelodysplastic syndromes, n = 26; thrombocytopenia, n = 14; and other, n = 7) fulfilling the Nordic criteria for germline investigation, based on (i) medical history or family history suggestive of a germline condition and (ii) relevant findings from the somatic diagnostic work-up (CytoMol), were recruited. The genetic analysis included enhanced whole-exome sequencing (n = 69) or sequencing of specific variants of interest (n = 16). RESULTS:Pathogenic or likely pathogenic (P/LP) germline variants were identified in 35% of patients (30/85). The diagnostic yield varied from 6% (1/16) in the family history group to 52% (17/33) in the CytoMol group. Germline DDX41 P/LP variants were the most frequent finding (13/30, 43% of all positive cases) almost exclusively found within the CytoMol group (12/13). Seven variants of unknown significance were also detected (TERT n = 2 and DDX41, RTEL1, ETV6, PARN, and SAMD9 n = 1). Five patients carried a P/LP variant in genes associated with another hereditary cancer syndrome (BRCA1 n = 3; PALB2 n = 1; and CHEK2; n = 1). Survival analysis showed a trend for longer survival among patients with acute myeloid leukemia and confirmed or suspected germline predisposition that underwent allogeneic stem cell transplantation. CONCLUSIONS:The implementation of the Nordic guidelines in a prospective Swedish cohort results in a high overall diagnostic yield (35%), proving the feasibility and utility of these or similar guidelines in a clinical setting.

To explore the relation between disease characteristics, comorbidities, mutations and overall survival (OS) in chronic myelomonocytic leukaemia (CMML), we collected data from a population-based cohort of 149 consecutive patients. TET2 mutation (TET2(MT)) was associated with higher haemoglobin, less leucocytosis and longer OS compared to no TET2(MT) (TET2(WT)), despite patients being significantly older. Patients with multihit TET2(MT) had the most favourable outcome (HR 0.55, CI 0.35-0.88, p < 0.05). Multihit TET2(MT) was associated with lower lactate dehydrogenase and less monocytosis, indicating multihit TET2(MT) as a separate disease entity. Autoimmune disease (AID) was present in 33.6% of patients, with no association to any mutations. In multivariable analysis, the number of TET2(MT) was demonstrated to be an independent factor associated with improved OS, and RUNX1(MT), myeloproliferative CMML (CMML-MP), ECOG >0 and transfusion dependence remained significant adverse factors. Internal validation including cross-validation and correction for optimism consistently demonstrated that a prognostic model containing the number of TET2(MT), RUNX1, CMML-MP, ECOG >0 and transfusion dependence showed better calibration, discrimination and overall performance than CPSS-Mol in predicting OS. Importantly, the addition of TET2 mutation status to CPSS-Mol also improved the CPSS-Mol score performance. Taken together, TET2(MT) status, especially multihit TET2(MT), defines a specific CMML phenotype and should be considered in future prognostic scores.

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.

BACKGROUND:The Molecular International Prognostic Scoring System (IPSS-M) is the new gold standard for diagnostic outcome prediction in patients with myelodysplastic syndromes (MDS). This study was designed to assess the additive prognostic impact of dynamic transfusion parameters during early follow-up. METHODS:We retrieved complete transfusion data from 677 adult Swedish MDS patients included in the IPSS-M cohort. Time-dependent erythrocyte transfusion dependency (E-TD) was added to IPSS-M features and analyzed regarding overall survival and leukemic transformation (acute myeloid leukemia). A multistate Markov model was applied to assess the prognostic value of early changes in transfusion patterns. RESULTS:Specific clinical and genetic features were predicted for diagnostic and time-dependent transfusion patterns. Importantly, transfusion state both at diagnosis and within the first year strongly predicts outcomes in both lower (LR) and higher-risk (HR) MDSs. In multivariable analysis, 8-month landmark E-TD predicted shorter survival independently of IPSS-M (p < 0.001). A predictive model based on IPSS-M and 8-month landmark E-TD performed significantly better than a model including only IPSS-M. Similar trends were observed in an independent validation cohort (n = 218). Early transfusion patterns impacted both future transfusion requirements and outcomes in a multistate Markov model. CONCLUSION:The transfusion requirement is a robust and available clinical parameter incorporating the effects of first-line management. In MDS, it provides dynamic risk information independently of diagnostic IPSS-M and, in particular, clinical guidance to LR MDS patients eligible for potentially curative therapeutic intervention.

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.

Background: Most available data on germline predisposition for myeloid neoplasms are based on retrospective studies. Moreover, due to great variability in resources and institutional policies, there is currently no consensus on how to investigate germline predisposition in the clinical setting. Aims: To prospectively investigate the clinical validity of the Nordic guidelines for germline testing in patients with suspected germline predisposition to myeloid neoplasms. Methods: Between October 2019 and January 2023, 84 sequential patients fulfilling the Nordic criteria for germline investigation were included in the study [acute myeloid leukemia (AML): n=38, myelodysplastic syndrome (MDS): n=33, thrombocytopenia: n=11, other: n=2]. In brief, the inclusion criteria were: (i) personal history indicative of a germline condition (criterion A1); (ii) “family history” defined as two or more first-degree (FDR) or second-degree relatives (SDR) with AML/MDS/thrombocytopenia or two FDR/SDR with other cancers, with at least one individual diagnosed before the age of 50 (criterion A2 and A3 respectively) or 3 FDR/SDR with AML/MDS/thrombocytopenia independently of age (A4); (iii) a potential germline variant detected during the somatic diagnostic work-up (Twist myeloid-panel, criterion B). Patients fulfilling A1-A4 were analyzed with whole exome sequencing (WES) including copy number variant analysis and analysis of non-coding regions in genes related to germline predisposition. Patients fulfilling criterion B were analyzed with targeted analysis. In patients with malignant disease the analysis was performed on genomic DNA from cultured fibroblasts (n=33), T-lymphocytes (n=3), or peripheral blood in remission (n=3). Genetic counselling was provided before and after the analysis. Results: As of today, the analysis is completed in 79/84 (94%) patients fulfilling one of the above criteria (A1: n=18; A2: n=6; A3: n=10; A4: n=15; B: n=30) from 13 Swedish institutions. A pathogenic or likely pathogenic (P/LP) germline variant according to the ACMG-criteria was identified in 29/79 (37%) patients. The detection rate of P/LP variants varied depending on the applied criterion: A1: 22%, A2-A3: 6%, A4: 47%, B: 57% (Figure 1). DDX41 variants were the most common aberration accounting for 50% of all positive cases (14/29) followed by ANKRD26: n=3, RUNX1: n=3, CEBPA: n=2, and ACTN1, DNAJC21, ETV6, PARN, TERT, SBDS: n=1 each). DDX41 aberrations were highly enriched (13/14) in patients fulfilling criterion B (13/14). Ten patients (13%) analyzed with WES carried a variant of unknown significance (VUS, TERT: n=2, RTEL1: n=2, SAMD9: n=1, SAMD9L: n=1, GATA2: n=1, RUNX1: n=1, PARN: n=1, ETV6: n=1) which warranted further investigation. Four patients carried a P/LP variant in genes not commonly associated with myeloid neoplasms (BRCA1, PALB2, PMS2, KCNQ1), a finding that prompted reassessment of the clinical management. Summary/Conclusion: The application of the Nordic guidelines for germline predisposition for myeloid neoplasms leads to the identification of a P/LP variant in more than one third of the patients with a detection rate depending on the applied criteria (range 6-57%). The spectrum of germline variants is criterion-depended, with DDX41 variants dominating among cases investigated due to the findings of the somatic profiling. In a significant proportion of patients with myeloid neoplasms and suspected germline predisposition the underlying genetic cause remains unknown despite the application of high-throughput sequencing.Keywords: Acute leukemia, Hereditary malignancies, Myelodysplastic syndrome

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.

Background: The cumulative red blood cells (RBC) transfusion burden is known to impact outcomes in myelodysplastic syndromes (MDS) but doesn't accurately predict prognosis during the early disease phase. Here we aimed to assess the prognostic value of early changes in transfusion patterns in addition to the recent IPSS-M scoring system. Methods: We gathered diagnostic biobank samples from adult patients (pts) with MDS and registered in the Karolinska Institute's biobank (KI) and the National Swedish MDS Biobank (NB) between 2003-2017 and 2013-2017, respectively. DNA targeted sequencing (152 genes) was performed (Bernard et al., NEJM Evid, 2022). Clinical data was retrieved through pts’ charts (KI) and the Swedish cancer registry (NB). Pts were treated according to Nordic/EU guidelines and most common therapies for lower-risk MDS and higher-risk MDS were erythropoietin and azacytidine, respectively. Transfusion data was obtained from the SCANDAT registry. Pts were followed with regards to RBC transfusion until censored due to death, transformation to acute myeloid leukemia (AML-t), allogenic stem cell transplantation (allo-SCT), or end of follow-up on the 31st of August 2018, whichever occurred first. As per the IWG hematological response criteria for MDS (Platzbecker et al., Blood 2019), transfusion states (TS) were categorized every 4 months (m) as transfusion dependent (TD) or transfusion free (TF) during the past 4 m period. Lower-risk MDS (LR) was defined as IPSS-M very low, low and moderate low, and higher-risk MDS (HR) as IPSS-M very high, high and moderate high at diagnosis (Bernard et al., NEJM Evid, 2022). Landmark analyses of overall survival (OS) were performed with the Kaplan-Meier method for estimating probabilities of OS over time. Multivariable analyses were conducted using Cox proportional hazards model. Results: We gathered a cohort of 688 pts with MDS from KI (n=424) and 33 other clinics in Sweden (NB, n=264). Median age at diagnosis was 74 years (y) old (range 19-93). The male:female ratio in the cohort was 1.4. At diagnosis, 63% of the pts were TF. Out of 646 pts evaluable by the IPSS-M score at diagnosis 54% had LR. Most frequently mutated genes in the cohort were TET2, SF3B1, ASXL1, DNMT3A, RUNX1, TET2, TP53 (66% TP53 multihit), U2AF1, STAG2, ZRSR2. Changes between TS (transitions) preferentially occurred within a year after diagnosis (panel A) with a median time for occurrence of transfusion-related transitions of 1.0 y (range 0.33-8.37). Based on this finding, we assessed whether TS at 8 m landmark impacted prognosis. We observed that there was a significant difference in OS since landmark between TF pts compared with TD pts at landmark 8 m and across IPSS-M categories (panel B). LR pts who were TD at 8 m, had a median OS of 3.2 y (95% CI: 2.2-4.0) versus 6.9 y (95% CI: 5.6-8.9) for LR pts who were TF (P<0.0001). Similarly, median OS was 0.8 y (95% CI: 0.6-1.1) in HR and TD pts while it was 2.4 y (95% CI: 2.1-3.1) in HR and TF pts at landmark 8 m (P<0.0001). Interestingly, OS for LR pts who were TD didn't significantly differ from HR pts who were TF at 8 m. Overall, pts TD at 8 m had more gene mutations compared to TF pts (median 5 [1;13] and 4 [1;16], respectively, P=0.0084). Moreover, studying specific genetic subgroups of MDS, TS at 8 m distinguished subsets of pts with adverse or favorable outcomes within SF3B1-mutated LR pts. In this population, the median OS in pts TF at 8 m was 8.4 y (95% CI: 6.5-13.1) compared to 3.2 y (95% CI: 1.7-4.1) for TD pts (P<0.0001). Next, in multivariable analysis, we found that TD at 8 m significantly impacted OS (HR=2.4 [95% CI: 1.9-3.1]), independently of diagnostic IPSS-M score, age, gender and type of MDS (de novo or therapy-related). Conclusion: TS at landmark 8 m, usually after outcome of first-line treatment was evaluated, appears to be a strong and independent predictor of OS in MDS. These findings are of particular importance for the LR group in which it could discriminate subsets with favorable outcomes from those with adverse prognosis. In addition to the IPSS-M calculation at diagnosis, transfusion dependency could be easily used for prognostic reassessment during follow-up. More generally, these results highlight the need of dynamic outcomes prediction tools and/or validation of current prognostic scores in dynamic settings. Finally, multistate modeling of the dataset is being completed and aims to assess how changes of transfusion patterns over time impact prognosis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Chronic myelomonocytic leukemia (CMML) is an aggressive disease in which survival after allogeneic hematopoietic stem cell transplantation (HCT) remains relatively poor. An assessment of prognostic factors is an important part of treatment decision making and has the potential to be greatly improved by the inclusion of molecular genetics. However, there is a significant knowledge gap in the interpretation of mutational patterns. This study aimed to describe outcomes of allogeneic HCT in patients with CMML in relation to clinical and molecular genetic risk factors. This retrospective study included 64 patients with CMML who underwent allogeneic HCT between 2008 and 2018, with a median follow-up of 5.4 years. Next-generation sequencing using targeted myeloid panels was carried out on saved material from 51 patients from the time of transplantation. Kaplan-Meier and Cox regression were used for analysis of overall survival (OS), and cumulative incidence with competing risks and Fine and Gray models were used for analysis of relapse and nonrelapse mortality (NRM). Mutations were detected in 48 patients (94%), indicating high levels of minimal residual disease (MRD) positivity at transplantation, even among those in complete remission (CR) (n = 14), 86% of whom had detectable mutations. The most frequently mutated genes were ASXL1 (37%), TET2 (37%), RUNX1 (33%), SRSF2 (26%), and NRAS (20%). Risk stratification using the CMML-specific Prognostic Scoring System molecular score (CPSS-Mol) resulted in 45% of patients moving to a higher risk-group compared with risk stratification using the CPSS. High leucocyte count (≥13 × 109/L), transfusion requirement, and previous intensive chemotherapy were associated with higher incidence of relapse. Being in CR was not linked to better outcomes. Neither ASXL1 nor RUNX1 mutation was associated with a difference in OS, relapse, or NRM, despite being high risk in the nontransplantation setting. TET2 mutations were associated with a significantly higher 3-year OS (73% versus 40%; P = .039). Achieving MRD-negative CR was rare in this CMML cohort, which may explain why we did not observe better outcomes for those in CR. This merits further investigation. Our analyses suggest that the negative impact of ASXL1 and RUNX1 mutations can be overcome by allogeneic HCT; however, risk stratification is complex in CMML and requires larger cohorts and multivariate models, presenting an ongoing challenge in this rare disease.

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 21·3 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 (0·62) 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 (0·69). 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.

Introduction One third of patients with myelodysplastic syndrome (MDS) will relapse after allogeneic stem cell transplantation (SCT), with a dismal prognosis. Early detection of relapse enables pre-emptive treatment and may potentially reduce relapse risk, but is limited by the lack of sensitive markers for minimal residual disease (MRD). We developed a pipeline where patient-specific mutations, as determined by a myeloid next generation sequencing (NGS) panel are tracked using sensitive digital droplet PCR (ddPCR). Method We designed a prospective Nordic study (NMDSG14B; NCT02872662) enrolling all patients with MDS, mixed MDS / MPN or AML with myelodysplasia related disease and < 30% marrow blasts undergoing SCT in the Nordic region. We hypothesized that personalized MRD detection by ddPCR can predict clinical relapse earlier than conventional methods. Patients were included before SCT and serial bone marrow samples were collected before, and 1 and 3 months post SCT, and thereafter every third month for 2 years or until relapse or death. Blood samples were collected monthly. The MRD results were not available for the treating physicians. MRD positivity was defined based on the background noise of the specific ddPCR-assays and varied between 0.05-0.1% VAF. Results Three-hundred and sixteen patients were screened between 2016 and 2020, of which 19 were excluded due to lack of mutation or disease progression preventing SCT. We here present data of 254 patients followed ≥ 6 months after SCT. Median age was 64 (18-78) years and 59% were male. Most WHO subgroups of MDS (n=166), MDS/MPN (n=39), AML (n=8) and therapy-related disease (n=41), were represented. Risk profile according to IPSS-R was very low (n=13), low (n=32), intermediate (n=46), high (n=60) and very high (n=32). The majority of patients received pre-SCT treatment consisting of HMA (n=159) and / or intensive chemotherapy (n=59) while 60 patients did not receive disease-modifying treatment prior to SCT. The most common mutations were ASXL1 (n=69), TET2 (n=58), SRSF2 (n=57) and TP53 (n=44). No mutation was identified in 10 pts, and NGS data is still pending for 11 patients. After a median follow-up of 436 days, estimated 2 years overall survival and relapse free survival were 72% and 63%, respectively. Cumulative incidence of NRM and relapse at 2 years was 16% and 20%, respectively. Forty-six patients relapsed after a median of 170 (53-733) days, and the estimated median survival following relapse was 197 days. The most common pre-SCT mutations in the relapsed cohort were TP53 (n=19), DNMT3A (n=11) and RUNX1 (n=9). Thirty-seven patients died due to non-relapse mortality (NRM) after a median of 83 (4-754) days. To date, MRD results are available for 64 patients. Relapse was preceded by positive MRD in 14 out of 15 patients a median of 79 (21-173) days before clinical relapse. The 15th patient had an extra-medullary relapse only. Borderline positive MRD samples < 0.2% VAF within 100 days after SCT followed by negative samples were seen in 11 non-relapse patients. Twenty-four of 37 patients in continuous complete remission (CCR) were consistently MRD neg. Six CCR patients had positive MRD after 100 days; two with transient borderline peaks (<0.1%) at 6 months; two with transient peaks > 0.1%, which turned negative when the patients developed GVHD; one patient with slowly decreasing MRD which turned negative first after 1 y, and finally one patient with prevailing KIT mutation (>700 days post-SCT) despite negative BCOR and STAG2. Two MRD+ patients died from NRM without showing signs of clinical relapse. Discussion In summary, we show that our pipeline of personalized MRD-assessment, based on patient-specific mutations is feasible with a high sensitivity to predict relapse. An update of study progression will be presented at the meeting. Figure 1 Disclosures Illman: Sanofi-Genzyme: Other: Travel Support; Celgene: Other: Travel Support. Mielke:DNA Prime: Honoraria, Other: received via my institution , Speakers Bureau; KIADIS Pharma: Honoraria, Other: received via my institution , Speakers Bureau; Miltenyi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: received via my institution , Speakers Bureau; Kite/Gilead: Honoraria, Other: received via my institution , Speakers Bureau; Bellicum: Honoraria, Other: received via my institution, Speakers Bureau; Novartis: Honoraria, Other: received via my institution, Speakers Bureau; Celgene/BMS: Honoraria, Other: received via my institution , Speakers Bureau. Ebeling:Accord Healthcare: Other: Travel Support; Amgen: Other: Travel Support; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Otsuka Pharma Scandanavia AB: Consultancy, Membership on an entity's Board of Directors or advisory committees.

OBJECTIVES:The study investigates the hypothesis that inflammation in myelofibrosis (MF) like in myeloma and lymphoma, may disturb iron distribution and contribute to anaemia. METHODS:A cross-sectional study of 80 MF and 23 ET patients was performed. RESULTS:About 35% of anaemic MF patients had functional iron deficiency (FID) with transferrin saturation <20 and normal or elevated S-ferritin (<500 µg/L). In ET, FID was rare. In MF patients with FID, 70.6% were anaemic, vs 29.4% in patients without FID (P = 0.03). Hepcidin was significantly higher in MF patients with anaemia, including transfusion-dependent patients, 50.6 vs 24.4 µg/L (P = 0.01). There was a significant negative correlation between Hb and inflammatory markers in all MF patients: IL-2, IL-6 and TNF-α, (P < 0.01-0.03), LD (P = 0.004) and hepcidin (P = 0.03). These correlations were also seen in the subgroup of anaemic MF patients (Table ). Tsat correlated negatively with CRP (P < 0.001). Symptom burden was heavier in MF patients with FID, and MPN-SAF quality of life scores correlated with IL-6 and CRP. CONCLUSIONS:The inflammatory state of MF disturbs iron turnover, FID is common and contributes to anaemia development and impairment of QoL. Anaemic MF patients should be screened for FID.

The myelodysplastic syndromes (MDS) have highly variable outcomes and prognostic scoring systems are important tools for risk assessment and to guide therapeutic decisions. However, few population-based studies have compared the value of the different scoring systems. With data from the nationwide Swedish population-based MDS register we validated the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R) and the World Health Organization (WHO) Classification-based Prognostic Scoring System (WPSS). We also present population-based data on incidence, clinical characteristics including detailed cytogenetics and outcome from the register. The study encompassed 1329 patients reported to the register between 2009 and 2013, 14% of these had therapy-related MDS (t-MDS). Based on the MDS register, the yearly crude incidence of MDS in Sweden was 2·9 per 100 000 inhabitants. IPSS-R had a significantly better prognostic power than IPSS (P < 0·001). There was a trend for better prognostic power of IPSS-R compared to WPSS (P = 0·05) and for WPSS compared to IPSS (P = 0·07). IPSS-R was superior to both IPSS and WPSS for patients aged ≤70 years. Patients with t-MDS had a worse outcome compared to de novo MDS (d-MDS), however, the validity of the prognostic scoring systems was comparable for d-MDS and t-MDS. In conclusion, population-based studies are important to validate prognostic scores in a 'real-world' setting. In our nationwide cohort, the IPSS-R showed the best predictive power.

Background: Myeloproliferative neoplasms (MPN) including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are clonal hemopathies characterized by burdensome symptom profiles and impaired quality of life. Few studies have evaluated patient-reported outcomes during treatment with non-experimental pharmacological regimens. Aims: The Myeloproliferative Neoplasm Quality of Life (MPN-QOL) Study Group aims to objectively quantify MPN symptom severity, frequency and quality of life at baseline and throughout treatment with non-experimental therapies utilizing the Myeloproliferative Neoplasm Symptom Assessment Form - Total Symptom Score (MPN-SAF TSS; JCO 2012). In this abstract, we provide updated results for the prospective international cohort trial currently in active enrollment: the MPN Experimental Assessment of Symptoms by Utilizing Repetitive Evaluation (MEASURE) trial. Methods: This study aims to recruit 180 international ET, PV, and MF (including primary MF and post-ET or post-PV MF) patients receiving non-experimental medical therapy and/or phlebotomy. Patients complete the MPN-SAF for seven consecutive days at enrollment and repeat the survey for an additional seven consecutive days between 90 days and six months. Patients also complete the European Organisation for Research and Treatment of Cancer (EORTC) and M.D. Anderson Symptom Inventory (MDASI) instruments at enrollment and on the first day of the second assessment. At visits, physicians acquired demographic, laboratory, physical examination, and radiographic data. Descriptive statistics were used to summarize data. Results: Clinical Data The MEASURE trial opened for enrollment in 2012 and remains in recruitment phase with 15 participating international sites. To date, 39 patients have been enrolled and 25 have completed both study visits. Participants include ET (28%), PV (24%), and MF (48%; 50% primary MF, 8% post-ET, 42% post-PV) patients. The majority of patients are male (64%) and of expected age (mean 69.3, range 39-89) for the disorders. Seventeen percent had prior thrombosis, 9% required red blood cell transfusion, and none reported prior splenectomy or hemorrhage. Mean hematologic measures included hemoglobin 13.2 g/dL, WBC count 11.4 x109/L, ANC 8.5 x109/L, and platelets 514 x109/L. Therapies received prior to enrollment included aspirin (n=16), hydroxyurea (n=11), phlebotomy (n=8), warfarin/clopidogrel/anticoagulation (n=8), erythropoietin (n=2), and interferon (n=1). The most common current MPN therapies were hydroxyurea (n=9), aspirin (n=9), interferon (n=4), and phlebotomy (n=2). Symptom Assessment In comparing MPN-SAF TSS mean symptom scores, all symptoms except bony pain improved between the first and second visits, including fatigue, early satiety, abdominal discomfort, inactivity, concentration, night sweats, itching, fever, weight loss, and overall quality of life (Figure1). Total MPN-SAF TSS scores improved from a mean of 32.3 to 25.9. On the EORTC, mean scores for physical, role, emotional, and social functioning improved from the first to the second visit (Figure 2). Cognitive functioning showed a slight decline. Global health status measure improved from 60.2 to 72.9. On the MDASI, symptom severity scores decreased from 3.6 to 2.8 from the first to second visit (Figure 3). Symptom distress measure decreased from 4.1 to 3.0. Discussion: Interim results from the MEASURE trial demonstrate that standard, non-experimental treatment regimens offer improvement in quality of life-related symptoms on multiple patient-reported survey instruments including the MPN-SAF TSS, EORTC QLQ-C30, and MDASI. Updated data including symptom correlations and mutational analysis to be presented at the 2016 ASH conference. Disclosures Ross:Novartis Pharmaceuticals: Honoraria, Research Funding; BMS: Honoraria. Radia:Novartis: Honoraria; Pfizer: Honoraria. McMullin:Novartis: Honoraria, Speakers Bureau. Cargo:Novartis: Honoraria; Celgene: Honoraria, Research Funding. Sekhar:Novartis: Research Funding. Mesa:Gilead: Research Funding; CTI Biopharma: Research Funding; Galena: Consultancy; Ariad: Consultancy; Incyte: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Promedior: Research Funding.

YKL-40 regulates vascular endothelial growth factors and induces tumor proliferation. We investigated YKL-40 before and after treatment with vorinostat in 31 polycythemia vera (PV) and 16 essential thrombocythemia (ET) patients. Baseline PV patient levels were 2 times higher than in healthy controls (P<0.0001) and 1.7 times higher than in ET (P=0.02). A significant correlation between YKL-40 at baseline and neutrophils, CRP, LDH, JAK2V617F and platelets in PV patients was observed, as well as a significantly greater reduction of YKL-40 levels in PV patients responding to therapy. YKL-40 might be a novel marker of disease burden and progression in myeloproliferative neoplasms.

Abstract Background In myeloproliferative neoplasms (MPN), Interferon-α (IFN-α) has been shown effective in inducing hematologic and molecular responses and in reducing vascular events. In clinical practice its use is mainly limited by intolerance due to side effects. Aim We sought to evaluate the tolerability of IFN-α therapy, the thromboembolic incidence and the causes of termination of therapy in a cohort of MPN, treated outside of clinical trials. Methods One hundred patients (M/F 41/59, median age 48 years, range 15-73) with a diagnosis of polycythemia vera (PV, n=47), essential thrombocythemia (ET, n=43) and myelofibrosis (MF, n=10) according to the WHO 2008 criteria, on current or previous treatment with IFN-α (IFN-α-2b, Peg-IFN-α-2b, Peg-IFN-α-2a) were included. The patients, diagnosed 1987-2012, were recruited from 9 centers in Sweden and Norway, and retrospectively analyzed. Hematologic response in PV and ET was assessed according to ELN criteria from 2009. Response to treatment in MF was defined as platelets ² 400x109 /L, white blood counts ² 10x109/L and transfusion independency. Results IFN-α treatment characteristics are displayed in Table 1. The median treatment duration for IFN-α was 34 months. Treatment prior to IFN-α had been received by 44 pts including hydroxyurea (n=34), anagrelide (n=19), busulphan (n=2), radioactive phosphorus (n=1), 10 pts having received more than one cytoreductive agent. Complete hematologic response (CR) was observed in 58 pts (PV=28/47, ET=30/43) and partial hematologic response (PR) in 15 pts (PV=2, ET=13). In MF, hematologic response was noted in 8 out of 10 patients. IFN-α related adverse events (AE) were recorded in 76 pts (76/100, 76%) with similar rates between genders (M 30/41, 73%, F 45/59, 76%). AE were generally of low grade. Twenty pts experienced multiple (³ 3) side effects (M/F 6/14), females reporting a total of 96 AE compared to 53 in males. Hematologic toxicity was low with 4 pts presenting with anemia, 4 with leukopenia and 3 with thrombocytopenia. Most common non-hematologic toxicities were fatigue in 30 pts (M/F 11/19), myalgia in 28 (M/F 11/17) and depression in 21 (M/F 4/17), followed by liver function test elevation (n=9), headache (n=9), alopecia (n=8) and skin reaction (n=7). In two pts with autoimmune co-morbidities (rheumatoid arthritis, psoriasis), flare-up of symptoms related to autoimmune activity were seen, leading to discontinuation of therapy. Only one vascular event occurred in a 64 year old woman with PV, in CR since 92 months, who developed a myocardial infarction after 94 months of IFN-α-2b treatment. A total of 43 pts (M 16/41, 39%, F 27/59, 46%) discontinued therapy, of whom 34 (M 13/41, 32%, F 21/59, 36%) due to side effects. The most common cause of discontinuation of therapy due to side effects was depression (15/21), followed by fatigue (12/30) and myalgia (9/28). Nineteen (19/34, 58%) of the pts who discontinued therapy due to side effects were in CR. Discontinuation due to other reasons than side effects were lack of efficacy/progression of disease (n=5), co-morbidities (n=2), CR including molecular response (n=2) and pregnancy (n=1). Out of the 53 pts with ET and MF, 25 were JAK2V617F mutated and 14 had a CALR-mutation. No significant differences between these two groups were seen regarding side effects or discontinuation rate. Out of the 57 pts remaining on IFN-α, 19 still received IFN-α-2b (19/35, 54%), 7 PegIFN-α-2b (7/12, 58%) and 31 PegIFN-α-2a (31/53, 58%). Conclusion In this retrospective cohort study, the treatment discontinuation rate due to side effects was higher than in previous reports. This may be explained by the relatively long median duration of treatment in this cohort, reflecting a poor tolerance of low-grade toxicity over time. Depression was frequent and the most common reported side effect when therapy was discontinued. Gender difference, with females reporting a higher incidence of depression and a larger total burden of AE, was noted. The frequency of thromboembolic events was very low in this IFN-α treated cohort. Table 1. IFN-α treatment characteristics. Type of Interferon Patiens (n) Dose per week–median (range) Treatment time-median IFN α-2b 35 9 MIE (1,2-20) 58 PegIFN α-2b 12 40 μg (30-80) 46 PegIFN α-2a 53 90 μg (30-135) 15 Disclosures No relevant conflicts of interest to declare.

The quality of life (QoL) at the time of diagnosis of myeloproliferative neoplasm (MPN) has, to date, not been studied. One hundred and seventy-nine patients with MPN: 80 with essential thrombocythemia (ET), 73 with polycythemia vera (PV), 22 with primary myelofibrosis (PMF) and four with MPN undifferentiated, were included in this study. European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQC30) and the MPN-Symptom Assessment Form (MPN-SAF) were used to evaluate QoL. Fatigue was the most reported symptom in these patients. Patients with PV reported significantly higher mean scores for inactivity, dizziness, cough, itching, depression and lower total QoL compared to patients with ET. Patients with PV had significantly more headache and itching compared to patients with PMF. When the newly diagnosed patients with MPN were compared with a cohort of patients with MPN with mean disease duration of 7.8 years, the differences were most striking for patients with PMF, with significantly more fatigue, abdominal discomfort, concentration problems, insomnia, fever, weight loss and lower overall QoL developed over time.