e19039 Background: Momelotinib (MMB) is a potent JAK1, JAK2 and ACVR1 inhibitor with clinical activity against the hallmark features of myelofibrosis (MF), namely anemia, constitutional symptoms and splenomegaly, across the continuum of JAKi naïve or previously JAKi treated intermediate/high risk MF patients as demonstrated in the previously conducted Phase 3 SIMPLIFY-1 & -2 clinical trials (S1, S2). S1 was conducted in JAKi-naïve patients with MF (n = 432) double-blind randomized 1:1 to MMB or ruxolitinib (RUX). MMB demonstrated a statistically non-inferior splenic response rate (SRR) to RUX at the W24 landmark analysis in S1 but did not meet significance for total symptom score (TSS) response. Low SRR and TSS response was observed for RUX in patients with low platelets, while MMB elicited consistent SRR and TSS response across the platelet subsets, comparable to the response in the ITT. Transfusion independence (TI) at W24 was higher for MMB vs RUX patients across all PLT strata. Methods: Progressive anemia is a common occurrence in MF with nearly all MF patients requiring transfusions as their disease advances. Given the prognostic importance of Hgb and transfusion status in MF patients including evidence that achieving or maintaining transfusion independence by Week 24 with momelotinib is associated with improved OS in S1 and S2, we expanded the previously reported retrospective platelet subset analysis to explore the W24 TI response rates for MMB and RUX randomized patients in S1 by baseline Hgb and PLT levels and transfusion status. Results: The data presented here suggest that the prognostically-important W24 TI rate was substantively higher in anemic patients receiving MMB versus RUX, irrespective of the degree of anemia. MMB is also more effective relative to RUX in achieving or maintaining TI in JAKi naïve patients irrespective of baseline PLT count or baseline transfusion status. Conclusions: Together with data suggesting that TI response at W24 with momelotinib is associated with a survival advantage, these data further support the potential TI benefits of inhibiting ACVR1 in addition to JAK1 and JAK2 with MMB in MF patients. Clinical trial information: NCT01969838, NCT02101268. [Table: see text]

Abstract 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-results reported in complete remission after two courses of intensive chemotherapy 229 were MRD-negative (70%), as defined by <0.1% cells with leukemia-associated immunophenotype in the bone marrow. MRD-results were reported to clinicians in real time. Multivariate statistical analysis adjusted for known established risk factors did not indicate an association between MFC-MRD and overall survival (HR: 1.00 [95% CI 0.61, 1.63]) with a median follow-up of 2.7 years. Knowledge of the importance of MRD status by clinicians and individualized decisions could have ameliorated the effects of MRD as an independent prognostic factor of overall survival.

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 Leukemia Registry. By strict clinical inclusion criteria we aimed to identify genetic markers further distinguishing AML with t(9;22) as a separate entity. Twenty-five patients were identified and next-generation sequencing using a 54-gene panel was performed in 21 cases. Interestingly, no mutations were found in NPM1, FLT3, or DNMT3A, three frequently mutated genes in AML. Instead, RUNX1 was the most commonly mutated gene, with aberrations present in 38% of the cases compared to around 10% in de novo AML. Additional mutations were identified in genes involved in RNA splicing (SRSF2, SF3B1) and chromatin regulation (ASXL1, STAG2, BCOR, BCORL1). Less frequently, mutations were found in IDH2, NRAS, TET2, and TP53. The mutational landscape exhibited a similar pattern as recently described in patients with chronic myeloid leukemia (CML) in myeloid blast crisis (BC). Despite the concomitant presence of BCR-ABL1 and RUNX1 mutations in our cohort, both features of high-risk AML, the RUNX1-mutated cases showed a superior overall survival compared to RUNX1 wildtype cases. Our results suggest that the molecular characteristics of AML with t(9;22)/BCR-ABL1 and CML in myeloid BC are similar and do not support a distinction of the two disease entities based on their underlying molecular alterations.

Abstract 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 population‐based registers were used, enabling analyses from diagnosis to either death or 5‐year follow‐up for survival, inpatient and outpatient costs, costs of prescribed drugs, sick leave, and early retirement. Costs per patient were stratified by age group, treatment options, and FLT3‐ITD status. The expected 5‐year costs per patient differed substantially between age groups. Patients aged 18–59 years had an expected mean cost per patient of €170,748, while age groups 60–69 years, 70–79 years, and >80 years incurred an expected mean cost of €92,252, €48,344, and €24,118, respectively, over 5 years. Patients <60 years undergoing stem cell transplantation had the highest costs (€228,525 over 5 years). About 60% of costs for these patients were from hospitalizations and 20% from sick leave and early retirement; cost per day was highest from the first admission to complete remission. This study provides a baseline for socioeconomic evaluations of novel therapies in AML in Sweden.

The British Journal of Haematology publishes original research papers in clinical, laboratory and experimental haematology. The Journal also features annotations, reviews, short reports, images in haematology and Letters to the Editor.

Hypomethylating agents (HMAs) are increasingly used in patients with acute myeloid leukaemia (AML). Still, the benefit of HMAs compared to conventional therapy is debated and results differ between studies (Kantarjian et al., 2012; Quintas-Cardama et al., 2012; Bories et al., 2014; Dombret et al., 2015; Almeida et al., 2017; Maurillo et al., 2018; Talati et al., 2020). In the present study, we report data on the use and benefit of HMAs from a large population-based cohort covering all elderly patients in Sweden during a 10-year period. In total, 3135 patients aged ≥60 years diagnosed with non-acute promyelocytic leukaemia (APL) AML between January 2008 and December 2018 reported to the Swedish AML Registry (>98% coverage (Juliusson et al., 2012)) were studied. In all, 302 patients (9.6%) had been given HMAs (azacytidine or decitabine) as first-line treatment, 1529 (49%) intensive chemotherapy (IC) and 1304 (42%) palliative care (PC; with or without low-dose cytarabine, hydroxyurea or other low-intensive chemotherapy). The use of upfront HMAs increased from 0.4% to 3.6% of patients 2008–2011 to 8% of patients diagnosed in 2012 and 21% of patients diagnosed in 2018 (Fig 1A). The increase in HMA treatment was paralleled by a decrease in PC. HMA was most commonly used in patients aged 75–84 years (Fig 1B) and the increased HMA usage was seen regardless of cytogenetic risk group (Fig 1C, Table S1). Characteristics of treatment groups are shown in Table S2. Patients treated with HMA were significantly older compared to IC patients (78 vs. 70 years, P < 0·001), but younger compared to PC patients (78 vs. 82 years, P < 0.001). PC patients had poorer World Health Organization Performance Status (WHO PS 2–4 in 75%) compared to HMA and IC patients (WHO PS 0–1 in 76% and 82%, respectively) and cytogenetically high-risk patients were equally frequent between treatment regimens. The 1-year survival in HMA patients was 34%, the 3-year survival was 5.9% and the median overall survival (OS) was 8.3 months (95% confidence interval [CI] 7.0–9.8); corresponding figures for PC patients were 6.4%, 0.8% and 1.6 months (95% CI 1.4–1.8) and for IC patients 50%, 22% and 12.0 months (95% CI 11.4–12.9), respectively (Fig 2A, Table S2). The proportion of early deaths (≤30 days), was lower in HMA-treated patients (4.0% compared to 39.2% and 8.9% in PC- and IC-treated patients, respectively). Multivariate analysis for survival in all 3135 patients showed age, WHO PS, cytogenetic risk and AML aetiology to be independent risk factors (all P < 0.001) (Table S3). Regarding treatment modality, IC versus HMA showed no significant difference (hazard ratio [HR] 0.88, 95% CI 0.75–1.03), while patients with PC did significantly worse compared to HMA (HR 2.72, 95% CI 2.35–3.15; P < 0.001). Prognostic factors differed between patients treated with HMA and IC (Table S4). In HMA-treated patients, high haemoglobin was associated with better OS (P = 0·001), whereas older age and higher lactate dehydrogenase conferred poorer OS (P = 0·011 and P < 0·001, respectively). Importantly, cytogenetic risk, WHO PS and AML aetiology had no impact on OS in HMA patients. In contrast, in IC patients, adverse cytogenetics, antecedent haematological disorder (AHD)-AML, higher leucocyte counts, lower albumin and worse WHO PS were independently associated with worse OS (Table S4). To reduce bias between treatment groups, propensity score matching (PSM) was used to compare HMA to IC and PC. We matched 275 HMA patients to IC and PC patients at a ratio of 1:2 (see Table S5 for details). Despite matching, the median age remained higher in HMA compared to IC patients (78 vs. 74 years, P < 0·001). Still, there was no statistically significant difference in median OS between HMA and IC patients (8·3 vs. 9·3 months, P = 0·08) (Fig 2B). To investigate if better matching on age would change outcome, a 1:1 matching of 193 HMA patients aged 60–80 years was also performed (Fig S1), but still without a statistically significant difference between HMA and IC (P = 0·1). In addition, cytogenetic risk did not impact on the degree of benefit of HMA treatment (Fig 2C). In matched HMA versus PC patients, HMA patients showed a clear benefit with a median OS of 8·3 months compared to 2·7 months with PC (P < 0·0001) (Fig 2B). These differences were seen regardless of cytogenetic risk group (Fig 2D). However, it should be noted that co-morbidities, being associated with increased mortality in patients with AML (Storey et al., 2017), and likely to be over-represented in PC patients, could not be matched for due to insufficient data in the Registry. Recently, Talati et al. reported that patients aged ≥70 years treated with HMA had superior OS compared to both intensive and palliative treatment regimens (Talati et al., 2020). In order to investigate if our present results would show similar results in patients aged ≥70 years, we performed a PSM analysis in patients aged ≥70 years, but found the same results with no significant differences between HMA and IC (data not shown). The reason for the difference compared to the Talati et al. study is unclear, but our present results are more in line with other previous studies outside of clinical trials (Quintas-Cardama et al., 2012; Maurillo et al., 2018). The strengths of our present study are its size, as well as the nationwide and truly population-based nature of the cohort, likely to reflect the real-world setting. Still, limitations include lack of information on type of HMA administered and the number of completed cycles. Concerning the type of HMA, azacitidine is dominantly used in Sweden and in a study of health records, 19 of 20 HMA-treated patients received azacitidine. In our present study, as well as most other HMA studies, molecular testing deciphering the full mutational landscape of the patients, including tumour protein p53 (TP53), runt-related transcription factor 1 (RUNX1) and additional sex combs like-1 (ASXL1) status, was lacking. In future studies, such molecular profiling will be important for improving risk stratification for HMA treatment. In summary, we show a steady increase in the usage of HMAs in a population-based setting. HMA treatment was similar to IC in terms of OS in multivariate analysis, as well as in a PSM analysis, while there was a clear benefit of HMA compared to palliative treatment. In addition, prognostic factors differed between patients treated with HMA compared to IC. The authors declare no conflicts of interest. Table S1. Cytogenetic risk stratification*. Table S2. Clinical characteristics and comparisons between treatment groups. Table S3. Cox regression analyses for overall survival of patients aged ≥60 years, n = 3135. Table S4. Cox regression analyses of overall survival for patients aged ≥60 years treated with either HMA or intensive chemotherapy upfront. HMA, n = 302. Table S5. Propensity score matched comparisons between patients treated upfront with hypomethylating agent (HMA) or intensive chemotherapy (IC)*. Figure S1. Propensity score matching (PSM) with optimal age matching. Comparison of overall survival in PSM groups between patients receiving hypomethylating agents or intensive chemotherapy. Analyses were restricted to patients aged 60–80 years for optimal age matching. Variables used for PSM were age, gender, WHO Performance Status, cytogenetic risk, previous myelodysplastic syndrome and previous myeloproliferative disorder. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Momelotinib (MMB), a JAK1, JAK2 and ACVR1 inhibitor, has demonstrated clinically comparable splenic and symptomatic benefits to ruxolitinib (RUX), the standard-of-care JAK1/JAK2 inhibitor for myelofibrosis (MF), a condition marked by splenomegaly, constitutional symptoms and progressive anemia and thrombocytopenia. MMB also uniquely restores iron homeostasis and red blood cell production, reduces or eliminates the need for transfusions and improves or maintains platelet (PLT) counts. Consistent with MMB's differentiated biological profile, low myelosuppressive potential and favorable hematological tolerability, prolonged, near-maximal MMB dose intensity can be maintained regardless of underlying PLT values. In contrast, RUX's hematological toxicity profile necessitates attenuated starting doses for thrombocytopenic (TCP) patients with PLTs <200 × 109/L and substantive, progressive dose reduction to mitigate against RUX-induced thrombocytopenia. Here we report post-hoc comparative efficacy analyses for RUX and MMB for spleen, symptom and transfusion independence (TI) response in patients with a baseline PLTs <150 × 109/L versus the ITT populations from the two previously-completed global Phase 3 SIMPLIFY studies. A retrospective analysis of spleen, symptom and TI response rates at week 24 was conducted in the TCP and ITT groups from SIMPLIFY-1 (S1), a double-blind Phase 3 study in intermediate/high risk MF patients randomized 1:1 to MMB or RUX over a 24-week treatment period, and SIMPLIFY-2 (S2), a Phase 3 study comparing MMB to best available therapy (BAT) in previously RUX-exposed MF patients. A baseline PLTs ≥50 × 109/L was required in S1, while there was no lower PLT limit for S2. Most subjects randomized to BAT (88%) received RUX during the 24-week randomized period. In S1, 9.5% and 24% of 432 subjects randomized had a PLT count of <100 and <150 × 109/L, respectively, at baseline. At week 24, MMB demonstrated a consistent splenic response rate (SRR) of 23% in patients with baseline PLTs <150 × 109/L and 27% in the ITT. A markedly reduced SRR was observed for the TCP group on RUX (4%) in comparison to the ITT (29%). Total symptom score (TSS) response rate was 28% in both the TCP and ITT in the MMB arm. In the RUX arm, the TSS response rate was lower in the TCP group (32%) than in the ITT (42%). MMB treatment elicited a TI response rate of 62% and 67% in the TCP and ITT groups, respectively, while for RUX the equivalent response rates were 43% and 49%. Of the 40 MMB subjects that discontinued therapy prior to week 24, 1 (2.5%) and 7 (17.5%) had a baseline PLTs <100 and <150 × 109/L, respectively. Of the 16 RUX subjects who discontinued therapy prior to week 24, 5 (31.4%) and 11 (69%) had baseline PLTs <100 and <150 × 109/L, respectively. In S2, 44% of 156 subjects randomized had a PLT count of <100 and another 22% had PLTs 100-150 × 109/L at baseline. The TSS response with MMB was 24% for the TCP and 26% in the ITT. Notably, this TSS response rate was retained even in patients with PLTs <100 × 109/L. Similarly, splenic and TI outcomes with MMB in the TCP were within 1-2% of the ITT response rates for these endpoints. Response rates in the control arm of S2 were low for both TCP and ITT (SRR 7 vs 6%, TSS 3 vs 6% and TI 22 vs 21%). These retrospective analyses of data from the two Phase 3 SIMPLIFY studies demonstrate that MMB efficacy is maintained in TCP patients and is comparable to that observed in the broader JAKi-naïve and previously JAKi-treated ITT populations in S1 and S2. These data contrast with RUX data from S1 where the SRR was markedly decreased and the TSS moderately decreased in TCP patients, consistent with reduced RUX dose intensity and higher rates of early discontinuation in this subset. Consequently, for patients in S1 with low PLTs, MMB and RUX demonstrated similar symptomatic benefit, while MMB had a more favorable profile for splenic volume reduction and TI. Response rates for the three parameters in the MMB arm of S2 were comparable between the TCP and ITT groups. Response rates in the control arm were low and not substantially different between the TCP and ITT groups, with most patients receiving very low dose intensity of RUX. Together, the findings of comparable spleen, symptom and TI response in the TCP and ITT groups treated with MMB suggest that the compound could become the optimal JAK inhibitor therapy for intermediate/high risk MF patients with underlying disease-related or prior RUX-induced thrombocytopenia. Disclosures Kiladjian: Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Platzbecker:Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Mayer:Principia Biopharma: Research Funding; AbbVie: Research Funding. Illés:Novartis, Janssen, Pfizer, Roche;: Other: Travel, Accommodations, Expenses; Takeda, Seattle Genetics: Research Funding; Celgene, Janssen, Novartis,Roche, Takeda: Consultancy; Janssen, Celgene, Takeda, Novartis Pharma SAS, Pfizer Pharmaceuticals Israel, Roche;: Consultancy, Honoraria. Vannucchi:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Nagy:MorphoSys AG: Patents & Royalties. Yoon:Novartis: Consultancy, Honoraria; Janssen: Consultancy; F. Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding; Amgen: Consultancy, Honoraria; Kyowahako Kirin: Research Funding; YuhanPharma: Research Funding. Von Bubnoff:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Clinical biomarker research, steering committee, Patents & Royalties: Research support, Research Funding; Astra Zeneca: Honoraria, Other: Lectures, Patents & Royalties: Astra Zeneca. Verstovsek:Promedior: Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; Celgene: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; CTI Biopharma Corp: Research Funding; Sierra Oncology: Consultancy, Research Funding; Gilead: Research Funding; Genentech: Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Novartis: Consultancy, Research Funding; ItalPharma: Research Funding; Blueprint Medicines Corp: Research Funding; NS Pharma: Research Funding. Klencke:Sierra Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Donahue:Sierra Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Mesa:Incyte: Research Funding; Bristol Myers Squibb: Research Funding; AbbVie: Research Funding; Sierra Oncology: Consultancy; Novartis: Consultancy; LaJolla Pharmaceutical Company: Consultancy; Samus Therapeutics: Research Funding; Promedior: Research Funding; Genentech: Research Funding; CTI BioPharma: Research Funding.

Improved survival of men 50 to 75 years old with acute myeloid leukemia over a 20-year period

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 cancer treatments, there are few estimates of the resource use and economic burden by treatment phase. Methods: This study was a retrospective database study performed on Swedish national data. Adult patients (age ≥18 years) diagnosed with AML in Sweden between 2007 and 2015 were identified in the Swedish Cancer Registry, along with vital status. Data on resource use were collected from national registers for inpatient- and outpatient specialized care and prescribed drugs. Information on diagnostics and treatment was accessed from the Swedish national AML Registry (SwAMLR). Data on sick leave (SL) and early retirement (ER) came from the Swedish Social Insurance Agency (absent days costed with the mean salary in Sweden). Hospital care resource use was costed using diagnosis-related group (DRG) remunerations, and include cost of inpatient drugs. The mean cost from the defined start of the treatment phase until the end of the treatment phase was divided by the mean number of days for the corresponding treatment phase to estimate the mean cost per day. The defined treatment phases were restricted to a maximum of 5 years. All costs are represented in US$. Results: Of the 2,954 patients identified in the Swedish Cancer Registry, 1,772 patients with a median age of 64 years were identified in the SwAMLR as fit for receiving high-dose chemotherapy . Of these, 1,243 were recorded with both curative intent of treatment and dates for achieving complete remission. Mean costs from the first AML-related hospital admission until the date of complete remission amount to $27,244. The mean number of days for the corresponding period were 45.16, resulting in a mean cost per day of $603 from first admission to first complete remission. The corresponding cost per day for patients recorded with curative intent but no complete remission (n=428) are $494. Time was counted from first AML-related admission until 90 days after first admission, or SCT or death, whichever occurred first. Costs after complete remission to either relapse, SCT, death or re-induction (n=1,237) amount to $50,793 for a mean of 438.63 days ($116/day). This treatment phase includes long-term survivors, whereas the costs from SCT, relapse or re-induction are not included. From relapse to death, the total cost is almost twofold for patients with re-induction (n=350) compared to palliative treatment (n=254). Cost per day amount to $179 for patients with palliative treatment and $256 for patients with re-induction treatment, respectively. The cost per day from date of SCT to death (n=511) is estimated to $192, incurred over a long period of time (mean number of days 844.02). The age of transplant recipients ranged between 18-71 years, with a median of 52 years. Conclusions: Costs of AML up to remission are feasible to estimate through DRG-costing methods, and studies have shown these costs are intense. Indeed this study shows that the highest cost per day is observed from first admission to complete remission. In addition results from our study show that there are high costs incurred also in the long-term, i.e. after remission. Of the included treatment phases the total cost from date of SCT to death is the largest, amounting to over $160,000. Approximately 20% are due to SL/ER, which is the second largest cost component after inpatient costs accounting for 60% of the total costs. Table. Disclosures Hernlund: ICON: Employment. Redig:ICON: Employment. Paulsson:Novartis: Employment. Vertuani:Novartis: Employment.

More than half of all Swedish adult patients with acute myeloid leukemia (AML) are 70 years or older at diagnosis. The incidence of AML currently peaks at age 80-84, and declines among even older adults, in accordance with the general cancer incidence by age. AML biology according to age has again come into focus due to the concept of age-related clonal hematopoiesis. We have previously shown that most patients up to 80 years tolerate and benefit from intensive chemotherapy, and the outcome has improved over the last twenty years, whereas patients older than 80 have a very poor outcome with no improvement over time. However, now new therapies with much less toxicity are available which could potentially be tolerated by the oldest patients, who therefore need to be better characterized. We previously reported the karyotypic profile in older patients. Herein we report the clinical and diagnostic features according to age with a specific focus on the very old (Table 1) and a comparison to younger patients. Data

Acute leukemia (AL) is a rare, potentially curable, aggressive neoplasm of hematopoietic origin. AL is a heterogeneous disease and is further subdivided according to clinical and biological features. The aims were to investigate: i) the incidence and survival of adult AL in regions with socioeconomic differences, ii) the outcome of acute promyelocytic leukemia (APL) with particular emphasis on the course of disease during the first weeks of diagnosis, iii) the disease characteristics and survival in patients aged 10-30 years, with acute myeloid leukemia (AML). We have investigated these issues in population-based materials; the first two studies were based on data from the Swedish Cancer Registry and the other four studies were based on data from the Swedish Adult Acute Leukemia Registry (SAALR). Comparisons were made with Estonia on incidence and survival of AL and with the Nordic Society for Paediatric Haematology and Oncology (NOPHO) and adult registries in Denmark and Norway for young AML patients. The incidence of de novo AL was higher in western Sweden than in Estonia for patients aged ≥ 65 years. The 5year relative survival for AL in patients aged 16-64 years was better in western Sweden than in Estonia and there was a significant improvement in outcome in western Sweden during 1982-1996. The differences in survival between the regions had decreased during the period 1997-2001; a dramatical improvement of survival was seen in Estonia, while no further improvement was recorded in western Sweden. In a population-based study of APL, 29% of patients died within 30 days from diagnosis, 41% due to hemorrhage. The early mortality was higher than described in randomized trials. There were no differences in survival for young AML patients whether treated according to pediatric or adult treatment protocols. Age was not found to be an independent prognostic marker for outcome. Studies from population-based materials provide real world data, an important complement to data from randomized trials. Observational studies from population-based registries with high coverage can improve the epidemiological knowledge and can also describe unknown problems that need further investigation in randomized trials.

Abstract 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 this further in a population-based material and if possible find factors associating with improvement. Patients and Methods We investigated temporal trends of early mortality defined as death within 30 days of diagnosis in the Swedish AML-registry. "Day of diagnosis" was defined as the day of the diagnostic bone marrow aspiration. The annual incidences of EM in 6034 non-promyelocytic AML patients (median age 71 years) in Sweden 1997-2014 were analyzed. Plots showing unadjusted cubic smoothing splines were constructed. Generalized estimation equation models were used to generate rate ratios with calendar year as the independent variable with 1997 as the reference year. Adjustments were made for age, gender, center, AML class (snomed), AML type (de novo/therapy related or secondary AML), WHO performance status, cytogenetic risk and treatment intensity. To avoid bias due to baseline characteristics missing not at random, multiple imputation (n=10) was performed for variables with missing data. A predefined subgroup analysis based on treatment intensity was also performed. Results We found an overall modest but significant reduction of early mortality with a yearly rate ratio (RR) of 0.99 (95% CI: 0.98-1.00, p=0.026) of the unadjusted EM (figure 1). Separate analysis of patients given induction treatment compared to those receiving palliative care showed that the reduction of early mortality was exclusively seen in the induction treatment group. Here, the crude yearly reduction of early mortality was RR=0.97 (95% CI:0.94-0.99, p=0.01) whereas there was no reduction in the palliative treatment group; RR=1.01(95% CI:0.99-1.02, p=0.27) (figure 2). Interestingly, the decrease of the early mortality rate was lost in the adjusted model; RR= 1.00 (95% CI:0.99-1.01, p=0.37) for the whole cohort. In univariate analysis two factors impacted the model in the direction of decreased EM; improved WHO performance status at diagnosis and a modest increase of low-risk cytogenetic patients (figure 3). Notable was also a slight decrease of the number of intensively treated patients during the time period. When adjusting for WHO PS and cytogenetic risk, subgroup analysis even showed an increased adjusted early mortality rate among palliatively treated patients, RR=1.02 (95%CI: 1.01-1.03, p=0.001) while there was no difference among the intensively treated patients, RR=1.00 (95% CI: 0.97-1.02, P=0.81) (figure 2). Simply put, if patients would have retained the same case mix as in 1997 the decrease of EM we see would not have occured. Caveats are that we assume that the WHO performance scale has been applied consequently during the study period. We have no indications otherwise and the scale is regarded as a robust and well validated instrument, so we consider this risk minor. The decrease in the number of intensively treated patients may also indicate a change in the selection process that theoretically could improve outcomes, for instance a more widespread use of EM risk assessment scales. This is however nothing the authors are aware of has happened on a general level during the time period. We conclude that a major factor associating with the decrease of early mortality in AML is a general improvement of performance status of patients at diagnosis. Disclosures No relevant conflicts of interest to declare.

Patients with secondary acute myeloid leukemia (AML) often escape inclusion in clinical trials and thus, population‐based studies are crucial for its accurate characterization. In this first large population‐based study on secondary AML, we studied AML with an antecedent hematological disease (AHD‐AML) or therapy‐related AML (t‐AML) in the population‐based Swedish Acute Leukemia Registry. The study included 3,363 adult patients of which 2,474 (73.6%) had de novo AML, 630 (18.7%) AHD‐AML, and 259 (7.7%) t‐AML. Secondary AML differed significantly compared to de novo AML with respect to age, gender, and cytogenetic risk. Complete remission (CR) rates were significantly lower but early death rates similar in secondary AML. In a multivariable analysis, AHD‐AML (HR 1.51; 95% CI 1.26–1.79) and t‐AML (1.72; 1.38–2.15) were independent risk factors for poor survival. The negative impact of AHD‐AML and t‐AML on survival was highly age dependent with a considerable impact in younger patients, but without independent prognostic value in the elderly. Although patients with secondary leukemia did poorly with intensive treatment, early death rates and survival were significantly worse with palliative treatment. We conclude that secondary AML in a population‐based setting has a striking impact on survival in younger AML patients, whereas it lacks prognostic value among the elderly patients. Am. J. Hematol. 90:208–214, 2015. © 2014 Wiley Periodicals, Inc.

To ascertain the clinical implications of high hyperdiploid (HH; 49–65 chromosomes) and triploid/tetraploid (TT; >65 chromosomes) adult acute myeloid leukemia (AML), all such cases were retrieved from the Swedish AML Registry. Of the 3,654 cytogenetically informative cases diagnosed between January 1997 and May 2014, 68 (1.9%) were HH (n = 50)/TT (n = 18). Patients with HH/TT were older than those with intermediate risk (IR) AML (median 71 years vs. 67 years; P = 0.042) and less often had de novo AML (63% vs. 79%; P = 0.004); no such differences were observed between HH/TT and complex karyotype (CK) AML. The overall survival (OS) was similar between patients with HH/TT and CK AML (median 0.9 years vs. 0.6 years; P = 0.082), whereas OS was significantly longer (median 1.6 years; P = 0.028) for IR AML. The OS was shorter for cases with HH than with TT (median 0.6 years vs. 1.4 years; P = 0.032) and for HH/TT AMLs with adverse abnormalities (median 0.8 years vs. 1.1 years; P = 0.044). In conclusion, HH/TT AML is associated with a poor outcome, but chromosome numbers >65 and absence of adverse aberrations seem to translate into a more favorable prognosis. Thus, HH/TT AMLs are clinically heterogeneous and should not automatically be grouped as high risk.Am. J. Hematol. 90:800–805, 2015. © 2015 Wiley Periodicals, Inc.

PURPOSE:Myeloproliferative neoplasms (MPNs) are associated with a shortened life expectancy. We assessed causes of death in patients with MPN and matched controls using both relative risks and absolute probabilities in the presence of competing risks.PATIENTS AND METHODS:From Swedish registries, we identified 9,285 patients with MPN and 35,769 matched controls. A flexible parametric model was used to estimate cause-specific hazard ratios (HRs) of death and cumulative incidence functions, each with 95% CIs.RESULTS:In patients with MPN, the HRs of death from hematologic malignancies and infections were 92.8 (95% CI, 70.0 to 123.1) and 2.7 (95% CI, 2.4 to 3.1), respectively. In patients age 70 to 79 years at diagnosis (the largest patient group), the HRs of death from cardiovascular and cerebrovascular disease were 1.5 (95% CI, 1.4 to 1.7) and 1.5 (95% CI, 1.3 to 1.8), respectively; all were statistically significantly elevated compared with those of controls. In the same age group, no difference was observed in the 10-year probability of death resulting from cardiovascular disease in patients with MPN versus controls (16.8% v 15.2%) or cerebrovascular disease (5.6% v 5.2%). In patients age 50 to 59 years at diagnosis, the 10-year probability of death resulting from cardiovascular and cerebrovascular disease was elevated, 4.2% versus 2.1% and 1.9% versus 0.4%, respectively. Survival in patients with MPN increased over time, mainly because of decreased probabilities of dying as a result of hematologic malignancies, infections, and, in young patients, cardiovascular disease.CONCLUSION:Patients with MPN had an overall higher mortality rate than that of matched controls, primarily because of hematologic malignancy, infections, and vascular events in younger patients. Evidently, there is still a need for effective disease-modifying agents to improve patient outcomes.

Allogeneic stem cell transplantation (SCT) is widely used as post-remission treatment in younger patients with poor or intermediate risk AML. Transplant decisions are mainly based on cytogenetic and molecular risk group, age, comorbidity and on the availability of a suitable donor. Secondary AML, including therapy-related AML (t-AML) and AML after an antecedent hematological disorder (AHD-AML), constitutes more than one fourth of the AML cases and is a predictor of a poor outcome. However, the extent to which SCT improves outcome of this patient group is poorly studied.

Abstract Background Patients with myeloproliferative neoplasms (MPNs) are reported to have a higher risk of thrombosis compared to the general population. However, the magnitude of the increase in risk in MPNs patients is not known since there is a lack of studies including control subjects. Therefore, we conducted a large population-based study to assess the risk of arterial and venous thrombosis in patients with MPNs in relation to matched controls. Patients and Methods All patients with MPNs reported to the Swedish Cancer Register and/or registered in the Inpatient Register from 1980 to 2009 were included. For each patient, four controls matched for age, sex, and county of residence, were randomly identified from the Register of Total Population. End of follow-up was December 31st 2010. Events of arterial and venous thrombosis, including deaths, were identified from the Inpatient and Outpatient Registers and the Cause of Death Register. Arterial thrombosis was defined as myocardial infarction, ischemic stroke, or peripheral arterial thrombus/embolus. Venous thrombosis was defined as pulmonary embolism, deep venous thrombosis (DVT), liver or splanchnic vein thrombosis, cerebral venous sinus thrombosis, or other venous thrombosis/embolus. Odd ratios (ORs) of arterial and venous thrombosis at diagnosis +/-30 days were calculated using logistic regression. Cox regression and flexible parametric models were used to estimate proportional and non-proportional hazard ratios (HRs) with 95% confidence intervals (CIs). Follow-up in all regression models started 30 days after diagnosis to avoid detection bias at time of diagnosis. Results A total of 11,155 patients and 44,620 matched controls were identified. Forty-six percent (n=5,161) were men and median age at MPN diagnosis was 69 years. The OR for arterial and venous thrombosis at time of MPN diagnosis +/- 30 days was 55.0 (95% CI 51.1-59.2 p<0.001) and 64.3 (42.2-98.1 p<0.001) respectively in MPN patients compared to controls. In MPN patients, the risk of arterial thrombosis was significantly 4.9-fold (4.8-5.0 p<0.001) increased compared to matched controls. The HR of myocardial infarction was 3.9 (3.7-4.1 p<0.001) and stroke 4.9 (4.8-5.0 p<0.001) in MPN patients. The HR of arterial thrombosis in MPN patients decreased shortly after diagnosis but thereafter increased with follow-up time in relation to controls (Figure 1a). There was a similar risk of arterial thrombosis in patients of different MPN subtypes compared to controls, the HR in patients with polycythemia vera (PV) was 5.0 (4.8-5.2), essential thrombocythemia (ET) 4.7 (4.6-5.0), primary myelofibrosis (PMF) 5.0 (4.7-5.3), and MPN-unclassifiable (MPN-U) 5.1 (4.8-5.5), respectively. The HR of venous thrombosis in MPN patients was 6.7 (6.2-7.2 p<0.001), where the HRs of pulmonary embolism was 7.5 (6.6-8.5 p<0.001) and DVT was 5.3 (4.8-5.9 p<0.001) compared to matched controls. MPN patients had a substantially increased risk of liver and splanchnic vein thrombosis, HR=41.4 (26.4-64.9 p<0.001). The risk of venous thrombosis in MPN patients decreased shortly after diagnosis and thereafter remained stable in relation to controls during follow-up time (Figure 1b). Compared to controls, patients with PV had a larger increase in risk of venous thrombosis than the other subtypes (HR=9.0; 8.0-10.1), while the HR of venous thrombosis in patients with ET was 5.4 (4.7-6.2), PMF 6.0 (4.9-7.5), and MPN-U 4.6 (3.7-5.7), respectively. Conclusions Patients with MPNs have an overall five- to sevenfold elevated risk of thrombosis compared to the general population. The highest HRs were seen for venous thrombosis, especially abdominal thrombosis. The odds of having a thrombosis at time of MPN diagnosis were high, indicating that thrombosis is an important first symptom of MPN. The elevated risk of arterial thrombosis increased while the elevated risk of venous thrombosis remained stable during follow-up time. This large population-based study is, to our knowledge, the first to quantify the excess risk of thrombosis in MPN patients compared to the general population. Our results indicate that we need to consider time after diagnosis in risk score models and rethink the strategies for thromboprophylaxis in patients with MPN in order to decrease the risk of thrombotic events. Figure 1A Risk of arterial (a) and venous (b) thrombosis in MPN patients compared to matched controls during follow-up time. Figure 1A. Risk of arterial (a) and venous (b) thrombosis in MPN patients compared to matched controls during follow-up time. Figure 1B Figure 1B. Disclosures No relevant conflicts of interest to declare.

Polycythemia vera, essential thrombocythemia, and primary myleofibrosis are chronic myeloproliferative neoplasms (MPNs) associated with an increased morbidity and mortality. MPNs are also associated with progression to acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). The "true" rate of transformation is not known mainly due to selection bias in clinical trials and underreporting in population-based studies. The outcome after transformation is dismal. The underlying mechanisms of transformation are incompletely understood and in part remain an area of controversy. There is an intrinsic propensity in MPNs to progress to AML/MDS, the magnitude of which is not fully known, supporting a role for nontreatment-related factors. High doses of alkylating agents, P(32) and combined cytoreductive treatments undoubtedly increase the risk of transformation. The potential leukemogenic role of hydroxyurea has been a matter of debate due to difficulties in performing large prospective randomized trials addressing this issue. The main focus of this review is to elucidate therapy-related leukemic transformation in MPNs with a special focus on the role of hydroxyurea.

Unsuccessful cytogenetics (UC) in patients with acute myeloid leukaemia (AML) treated on different SWOG trials was recently reported to be associated with increased age and dismal outcome. To ascertain whether this holds true also in unselected patients with AML, we retrieved all cytogenetic reports in cases from the population-based Swedish AML Registry. Between 1997 and 2006, 1737 patients below 80 yr of age without myelosarcoma or acute promyelocytic leukaemia received intensive treatment. The frequencies of UC and unperformed cytogenetics (UPC) were 2.1% and 20%, respectively. The early death rates differed between the cytogenetic subgroups (P = 0.006) with the highest rates in patients with UC (14%) and UPC (12%) followed by high-risk (HR) AML, intermediate risk (IR) and standard risk (SR) cases successfully karyotyped (8.6%, 5.9%, and 5.8%, respectively). The complete remission rate was lower in UC and UPC and HR compared with the other risk groups (P < 0.001). The overall five-year survival rates were 25% for UC and 22% for UPC, whereas the corresponding frequencies for SR, IR and HR AML patients without UC and UPC were 64%, 31% and 15%, respectively. In conclusion, lack of cytogenetic data translates into a poor prognosis.

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.1-5. This is repeated once, and followed by consolidation with slightly abbreviated DA to a total of 4 courses. Recommendations include full dose treatment to most patients up to 80 years, and allogeneic transplantation to fit patients with high- and intermediate-risk genetics. Guidelines are summarized in English at www.cancercentrum.se/sv/Vardprogram/AML (pdf file pp. 116-9). These guidelines replaced (multi)regional and local programs.