ALBERT

Description: Abstract 3542 The prognosis of acute promyelocytic leukemia (APL) has improved markedly over the last two decades. Clinical trials have demonstrated excellent survival of patients receiving anthracycline-based chemotherapy in combination with all-trans-retinoid acid (ATRA). It is not clear whether the excellent survival results demonstrated in clinical trials during recent years, also do apply to unselected patients including elderly and frail patients for whom a clinical trial may not be available. In order to investigate survival and death rates in APL over the course of treatment, we conducted a retrospective analysis of survival in 105 consecutive APL-patients diagnosed in Denmark January 2000 through June 2012. Data were retrieved from the Danish National Acute Leukemia Registry which covers 95 – 100 % of all acute leukemia cases diagnosed in Denmark since January 2000 (not including children). A diagnosis of APL was confirmed in 105 (3.9 %) of 2726 adult patients (age ≥ 15 years) with acute myeloid leukemia (AML) diagnosed in Denmark during the 12½ year period. This corresponds to an incidence rate of 1.53 APL cases per million inhabitants per year. The diagnosis of APL was based upon cytogenetic analysis (performed in 96 (91 %) of cases), and/or interphase FISH (iFISH), and/or RT-PCR in a total of 100 cases. In 5 cases clinical signs and morphological changes in bone marrow were highly suggestive of APL and these cases were, thus, deemed to have APL. Median age at diagnosis of APL was 50 years (range 15 to 83 years) and median leukocyte count was 2.65 (range 0.2 to 99.0 × 109/L). In 104 patients with data available for analysis, very early death (VED, within the first week from the date of diagnostic bone marrow) occurred in 10 cases (9.6 %), and early death (ED, death within 30 day from diagnosis) occurred in 22 (21 %) cases. Death between day 30 and 5 years from diagnosis occurred in 11 cases. No deaths were seen after 5 years from diagnosis. For all patients, estimated overall survival at 10 years was 65 % (Figure 1). Patients surviving beyond day 30 from day of diagnosis (82 cases) had an excellent overall survival of greater than 80 % at 10 years (Figure 2). Survival of patients were strongly correlated with WHO-performance status whereas age over 50 years and presenting leukocyte count greater than 10 × 109/L could not be definitely associated with inferior survival (Table 1 and Figure 3). Table 1. Factors of importance to survival in unselected APL-patients Probability of overall survival (Univariate Cox Regression, nevaluable= 104) Probability of overall survival (multivariate Cox Regression, nevaluable= 101) Variable Hazard ratio 95% CI of HR P value Hazard ratio 95% CI of HR P value Age (≤50 vs. 〉50 years) 2.17 1.07–4.42 0.03 1.44 0.67–3.09 NS WHO performance status (0–1 vs. ≥2) 5.20 2.57–10.5 〈 10−4 4.06 1.88–8.78 〈 10−4 WBC (≤10 × vs.〉10 × 109/L) 1.76 0.86–3.61 NS 1.62 0.79–3.33 NS From this population-based analysis we conclude that early death continues to be the predominant hazard to patients with APL. Two thirds of deaths in APL-patients do occur during the first month from diagnosis. Patients with a poor performance status at disease presentation carry a particularly dismal prognosis. For all APL-patients, every possible effort should be made to facilitate prompt diagnosis and speedy initiation of treatment with ATRA and anthracycline-based chemotherapy. When timely applied, currently available treatments are highly effective and result in cure in a high proportion of patients including elderly patients and patients with high leukocyte count at time of disease presentation. Disclosures: No relevant conflicts of interest to declare.

Description: Although chronic myeloid leukemia (CML) originates from a primitive hematopoietic stem cell (HSC), it is the more differentiated progenitor cells that drive the expansion of the malignant clone. In addition, previous studies of chronic phase CML have shown that, despite the marked leukocytosis observed here, megakaryocyte-erythroid progenitors dominate the progenitor fraction. We sought to elucidate this by employing the new marker for leukemic stem cells, the human myeloid inhibitory C-type lectin-like receptor (hMICL), in the study of progenitor cell expansion in CML. Bone marrow or peripheral blood stem cells were acquired from 11 normal donors and 31 CML patients at diagnosis in chronic phase and/or after 3-119 months of tyrosine kinase inhibitor (TKI) treatment. Cells were stained with fluorescent monoclonal antibodies and FACS sorted into HSCs (CD34+CD38-), hMICL+ progenitors (MpP; CD34+CD38+hMICL+), and hMICL- progenitors (MnP; CD34+CD38+hMICL-). Sorted cell subsets were subjected to growth in a 14-day methylcellulose assay and analyzed quantitatively for expression of the BCR-ABL fusion transcript. In normal donors, hMICL expression reproducibly identified a well-defined subpopulation of the CD34+CD38+ cells (fig 1A). The MpPs were highly enriched for cells of granulocyte-macrophage progenitors (GMP) phenotype compared to the MnPs (p=0.012) (fig 1B). Sorted MpPs produced almost exclusively granulocyte and/or macrophage (CFU-GM) colonies (median: 92% of colonies), while colonies from MnPs were dominated by BFU-Es (91%) and, as opposed to the MpPs, also contained CFU-GEMM colonies (0.64%) (fig 1C). Thus, hMICL seems to be a useful marker for the GMP population.Figure 1Immunological and functional properties of MpPs in normal donors. (A) Identification of MpPs, MnPs, and HSCs within the CD34+ compartment. (B) Cells with GMP phenotype (CD34+CD38+CD123lowCD45RA+) in MpP and MnP subsets. (C) Colony growth of bone marrow mononuclear cells (MNC) and sorted MpPs and MnPs in a 14-day methylcellulose assay. Error bars denote SDs.Figure 1. Immunological and functional properties of MpPs in normal donors. (A) Identification of MpPs, MnPs, and HSCs within the CD34+ compartment. (B) Cells with GMP phenotype (CD34+CD38+CD123lowCD45RA+) in MpP and MnP subsets. (C) Colony growth of bone marrow mononuclear cells (MNC) and sorted MpPs and MnPs in a 14-day methylcellulose assay. Error bars denote SDs. In CML at diagnosis we found decreased numbers of MpPs (mean 23% of CD34+CD38+ cells (range: 6.3-48%)), compared to the normal donors (33% (18-48%), p=0.030) (fig 2A). Extraordinarily, the MpP fraction varied considerably in size among CML patients, and 12/23 patients had MpP fractions within the 90% reference range (RR) of normal donors (MpPHIGH patients) and thus distinctly higher than the remaining patients (MpPLOW patients) (fig 2B-C). High MpP fractions significantly correlated with high WBC (Spearman's r = 0.47, p=0.049) (fig 2D), high neutrophil counts (r = 0.55, p=0.043), large spleen size (r = 0.66, p=0.0069), and low hemoglobin at the time of diagnosis (r = -0.58, p=0.014). Within the progenitor compartment, high ratio of BCR-ABL in the MpP to BCR-ABL in the MnP significantly correlated with large MpP fractions (r = 0.54, p=0.021).Figure 2Human MICL expression in chronic phase CML patients. (A) Fraction of MpPs in normal donors and CML patients at diagnosis. (B) Typical immunological profiles of MpPLOW patients and (C) MpPHIGH patients. (D) Correlation between MpP fraction size and total white blood cell count at the time of diagnosis. (E) Development of MpP fraction size in individual patients after 3-6 months (solid lines) and after 12-119 months (dotted lines) of TKI treatment in MpPLOW patients and (F) MpPHIGH patients.Figure 2. Human MICL expression in chronic phase CML patients. (A) Fraction of MpPs in normal donors and CML patients at diagnosis. (B) Typical immunological profiles of MpPLOW patients and (C) MpPHIGH patients. (D) Correlation between MpP fraction size and total white blood cell count at the time of diagnosis. (E) Development of MpP fraction size in individual patients after 3-6 months (solid lines) and after 12-119 months (dotted lines) of TKI treatment in MpPLOW patients and (F) MpPHIGH patients. During the first 6 months of TKI treatment differing developments in MpP fraction size were observed for MpPLOW and MpPHIGH patients. While MpPLOW patients showed increasing MpP fractions during the first 6 months of treatment (fig 2E), 4/4 and 2/4 MpPHIGH patients displayed a decrease in MpPs at 3 and 6 months, respectively (fig 2F). Thus, in these patients, the majority of the Ph+ progenitor cells being cleared seemed to be GMPs. In conclusion, our data demonstrate that hMICL is an early marker of granulocyte-macrophage differentiation, and provides a readily accessible approach to assessing the GMP population during TKI therapy in CML. Using the present approach we have uncovered a higher degree of variability in the composition of the progenitor compartment at diagnosis than previously reported, and shown that a significant proportion of the patients have expanded GMP populations. Ongoing studies are aimed at determining whether these patients may represent patients with a more advanced form of disease at the time of diagnosis. Disclosures: Stentoft: Novartis: Consultancy, Financial support for relevant congress participation Other, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bristol-Myers-Squibb: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Danish Regions: Membership on an entity’s Board of Directors or advisory committees. Hokland:Novartis: Research Funding.

Description: Abstract 2003 The prognosis of patients suffering from AML with manifestations of accompanying extramedullary leukemia (EML) including myeloid sarcoma (MS) compared to that of AML patients not exhibiting EML manifestations is still an open question as results from previous studies have been contradictory most likely due to selection bias. Here we present an analysis performed in a cohort of 2261 patients representing 〉90% of all AML patients diagnosed and treated in Denmark during the eleven-year period January 2000 through December 2010. The goal was to investigate the prognostic impact of presence of EML at time of AML diagnosis by a retrospective population- and registry-based analysis Of these patients, 219 (9.7%) showed signs of EML at time of AML presentation. Anatomic sites of EML were: lymph nodes (3.0%), skin (2.7%), spleen (1.7%), oral (1.3%), CNS (0.4%), testes (0.2%), other sites (1.1%), and two or more anatomical sites (0.5%). In 27 cases myeloid sarcoma was not accompanied by AML in the bone marrow and, thus, presented as isolated MS. In total, 1168 of the 2261 (52 %) patients were treated with curative intention. Allogeneic stem cell transplantation (Standard allo in 105 cases, and reduced intensity conditioning (RIC) transplant in 90 cases) was conducted in a total of 195 patients (118 in CR1, 65 in CR2, and 12 during other disease stages). Overall the frequencies of allogeneic transplantations in curatively treated patients were 13.7% in patients with EML and 8.5% in patients without EML. The presence of EML at time of leukemia diagnosis had no statistical significance to probability of obtaining complete remission (CR), nor to duration of overall survival (OS) (Table 1. and Fig. 1). By contrast, well-established prognostic parameters such as presenting cytogenetic abnormalities (categorized according to revised MRC-criteria, D. Grimwade et al. Blood, 2010), age, leukocyte count, and type of leukemia (secondary vs de novo) were all found to be statistically significant to probability of attainment of (CR) and to duration of OS in uni- as well as multivariate analyses. Gender was of borderline statistical significance with respect to probability of attainment of CR and to OS (Table 1).Figure 1Years from AML diagnosisPatients with EML(n = 132)Patients without EML(n = 1007)p-value (log-rank test) = 0.51Figure 1. Years from AML diagnosis. / Patients with EML. / (n = 132). / Patients without EML. / (n = 1007). / p-value (log-rank test) = 0.51Table 1.Factors of significance to probability of attainment of CR and to overall survival (OS)Probability of CR (Logistic regression, nevaluable = 927)Probability of overall survival (Cox regression, nevaluable = 958)VariableOdds ratio (OR)95% CI of ORP valueHazard ratio95% CI of HRP valueEML––0.82––0.54Age1.061.04–1.08

Description: Smoking is a well-established risk factor for cancer, and cancer patients have a high risk of venous thromboembolism (VTE). Conflicting results have been reported on the association between smoking and risk of VTE, and the effect of smoking on VTE-risk in subjects with cancer is scarcely studied. We aimed to investigate the association between smoking and VTE in subjects with and without cancer in a large population-based cohort. The Scandinavian Thrombosis and Cancer (STAC) cohort included 144,952 participants followed from 1993–1997 to 2008–2012. Information on smoking habits was derived from self-administered questionnaires. Active cancer was defined as the first two years following the date of cancer diagnosis. Former smokers (n = 35,890) and those with missing information on smoking status (n = 3680) at baseline were excluded. During a mean follow up of 11 years, 10,181 participants were diagnosed with cancer, and 1611 developed incident VTE, of which 214 were cancer-related. Smoking was associated with a 50% increased risk of VTE (HR 1.49, 95% CI 1.12–1.98) in cancer patients, whereas no association was found in cancer-free subjects (HR 1.07, 95% CI 0.96–1.20). In cancer patients, the risk of VTE among smokers remained unchanged after adjustment for cancer site and metastasis. Stratified analyses showed that smoking was a risk factor for VTE among those with smoking-related and advanced cancers. In conclusion, smoking was associated with increased VTE risk in subjects with active cancer, but not in those without cancer. Our findings imply a biological interaction between cancer and smoking on the risk of VTE.