ALBERT

Description: Introduction Blood eosinophilia may arise from clonal intrinsic disorders or reactive extrinsic conditions. The eosinophilic granulocytes (eosinophils) may have diverse physiological functions and cause organ involvement. A dose-dependent relation between eosinophilia and risks of end-organ damage has not been described and it is not known whether numbers below internationally used threshold criteria for eosinophilia in adults (

Description: Abstract 2835 Background: The classical chronic myeloproliferative neoplasms (CMPNs), including essential thrombocytemia (ET), polycythemia vera (PV), and chronic myeloid leukemia (CML), are disorders characterized by accelerated proliferation of hematopoietic tissue. Systemic mastocytosis, also a chronic myeloproliferative neoplasm, has been associated with increased risk of osteoporosis. However, to our knowledge, no data is available on the risk of osteoporosis among patients with classical CMPNs. Method: We conducted a Danish population-based cohort study of the risk of osteoporosis among patients with ET, PV, and CML using data from the Danish health care system. ET, PV, and CML patients were identified from Danish National Registry of Patients (DNRP), and linked to the Danish Civil Registration System (CRS) in the study period 1 January 1980 to 31 December 2010. Each Danish resident has a unique, permanent 10-digit civil registry number allowing unambiguous individual-level linkage among all Danish registries. Patients with a first-ever CMPN diagnosis in the DNRP were identified by means of their ICD-8 diagnosis code until 1994 and ICD-10 diagnosis code thereafter. By this means, we established three distinct cohorts of ET, PV, and CML patients. For each CMPN patient, 50 general population comparison cohort members without CMPN were identified in the CRS matched on age, sex, and calendar year, creating three comparison cohorts. Follow-up started 1-year from the date of diagnosis for CMPN patients. The comparison cohort members were assigned the same index date as their index CMPN case. A diagnosis of proximal femoral fracture was used an indicator of osteoporosis, since this fracture type invariably leads to hospitalization, and therefore would be registered in the DNRP throughout our observation period. The CMPN and comparison cohorts were followed until a diagnosis of femoral fracture, emigration, death, or 31 December 2010, whichever came first. Patients and comparison cohort members with a previous diagnosis of osteoporosis or osteoporotic fractures were excluded. The Kaplan-Meier method was used to estimate the cumulative rate of fractures. Cox regression was used to estimate hazard ratios (HRs) as a measure of relative risk of femoral fracture for each CMPN cohort compared to the comparison cohort, adjusted for comorbidity. Results: We identified 7,595 MPN patients (1,864 with ET; 4,418 with PV; and 1,313 with CML) and 338,974 comparison cohort members. The cumulative rate of proximal femoral fractures was higher among CMPN patients than among comparison cohort members, as depicted in the Figures. The rate of fractures per 1,000 person-years were: 6.6 (95% confidence interval (CI): 5.2–8.3) for ET patients [comparison group: 5.3 (95% CI: 5.1–5.4)], 9.9 (95% CI: 8.8–11.0) for PV patients [comparison group: 6.2 (95% CI: 6.1–6.3)]; and 8.2 (95% CI: 6.0–10.7) for CML patients [comparison group: 4.4 (95% CI: 4.3–4.6)]. The resulting adjusted hazard ratios (HR) were: HRET = 1.2 (95% CI: 0.9–1.5), HRPV = 1.8) (95% CI: 1.6–2.0), and HRCML = 2.7 (95% CI: 2.0–3.6). Conclusion: CMPN patients are at higher risk of osteoporotic fractures than the general population. Disclosures: No relevant conflicts of interest to declare.

Description: Rationale: Dasatinib (DAS) and interferon have different modes of action and may have synergistic activity in CML, due to both antineoplastic and immunostimulatory mechanisms. Addition of pegylated interferon (PegIFN) to imatinib therapy in CP-CML has in previous clinical trials (French SPIRIT and NordCML002) resulted in deeper molecular responses. Thus, an optimal combination of DAS and PegIFN may increase the proportion of patients who reach deep molecular response with potential for treatment-free remission (TFR). Design: Newly diagnosed CP-CML patients were treated with DAS (Sprycel, BMS) 100 mg OD as single drug for three months. Thereafter weekly subcutaneous injections of Peg-IFN α2b (PegIntron, MSD) were added to DAS; from end of month 3 (M3) to M6, 15µg/week, thereafter 25µg/week until M15. Primary end points were safety and the rate of MMR at M12. The doses of PegIFN were lower than in the SPIRIT and NordCML002 studies to increase adherence. Population: Forty patients were included at 14 university centers. One patient was lost to follow-up after M6. All patients were included in analysis up to M12. Mean and median age was 48 years (range 19-71). The proportions of high risk patients were 25% (Sokal), 15% (Hasford), and 15% (EUTOS). Safety and dosing: Treatment was well tolerated with expected DAS and PegIFN related side effects. Six patients had seven serious adverse events (AEs), all hospitalizations. 1 episode each of bradycardia/atrial fibrillation (possibly PegIFN-related), headache (DAS), fever (PegIFN), anaphylaxis-like reaction (PegIFN), fever/malaise/headache (PegIFN), pneumonia and a knee effusion (both unrelated). One pleural effusion occurred (grade 2, 3%). Grade 3-4 neutropenia and thrombocytopenia occurred in 6 and 9 patients respectively. Prolonged hematological toxicity (〉2 months) occurred in 8 patients, causing dosing problems in 5. One patient suffered grade 3 depression. Grade 3 flu-like symptoms occurred in 2 patients. One patient had lipase elevation grade 3 and one patient developed hypothyroidism attributed to PegIFN. Grade 2 dermal AEs like rash and acne occurred in about 20%, attributable to both drugs. 94% (DAS) and 76% (PegIFN) of assigned dose was given. Dose reductions occurred in 19 patients for DAS and 20 patients for PegIFN. Two patients discontinued DAS and switched to nilotinib, 1 for headache at M3 and 1 at M12 for lack of efficacy/hematological toxicity. Two patients could not start PegIFN for hematological toxicity (one lost to follow-up after M6). PegIFN was discontinued because of bradycardia/atrial fibrillation (1 patient), anaphylaxis (1 patient), flu-like syndrome (2 patients) and long-term hematological toxicity (2 patients). At 12 months 31/38 pats (82%) were still on PegIFN, a higher proportion than in the French Spirit or NordCML002 studies. Efficacy: We have used the DAS arm of the Dasision study (Kantarjian NEJM 2010) as a historical control. Early response at M3 was very similar between studies. In the present and the Dasision cohorts respectively, 18% vs 16% missed the 10% BCR-ABLIS landmark, 66% vs 56% achieved a CCyR and 8% vs 8% achieved MMR. At M6, three months after introduction of PegIFN, a steep increase in MMR rate was observed compared with Dasision. This was also reflected in deep responses, MR4.0 (see tables) and MR4.5 at M12, 18% vs 5%. The primary efficacy endpoint was MMR at M12, 82% vs 46%. Table 1.MMRDAS+PegIFN (%)DAS (Dasision)(%)Difference (%)M3880M6532726M9663927M12824636Table 2.MR4.0DAS+PegIFN (%)DAS (Dasision) (%)Difference (%)M3303M620614M938830M12481236 Progressions and treatment failure defined by ELN 2013: Failures: No progression was noted. At M3, 2 patients still had 〉95% Ph+ metaphases (MF). At M6, four patients (11%) had 〉 35% Ph+MF or 〉10% BCR-ABL levels. At M12, one patient failed CCgR and two more patients failed

Description: Background: In chronic myeloid leukemia (CML) the combination treatment of tyrosine kinase inhibitors (TKIs) with interferon-α (IFN-α) has proved to be effective and well-tolerated. IFN-α has long-term immunomodulatory effects, and when combined to TKI therapy, it may increase the success rates for treatment free remission. In our recent clinical trial NordCML007, a low-dose pegylated IFN-α was combined with dasatinib therapy. As dasatinib is also known to have immunostimulatory effects (activation of T and NK cells and downregulation of regulatory T cells), we aimed to monitor the immune effects of dasatinib and IFN-α combination treatment. Methods: 40 newly diagnosed CML patients participated in the NordCML007 clinical trial (NCT01725204). Patients were treated with 100 mg dasatinib QD and after 3 months IFN-α treatment was added (first 3 months 15 μg/week, then 25 μg/week of pegylated IFN-α). After 12 months of combination treatment, patients resumed to dasatinib monotherapy. In this immunological substudy, peripheral blood samples were collected at the diagnosis, 3, 12, and 24 months after the start of therapy. T- and NK-cells were phenotyped with multicolor flow cytometry, and their function (degranulation and cytokine secretion) was studied. In addition, a multiplexed cytokine and growth factor panel was performed (Proseek Multiplex Inflammation I96×96, Olink). Results: Dasatinib monotherapy led to an increase of NK-cell frequencies when compared to pre-treatment values (median diagnosis 6.8% vs. 3 months 12.8%, p

Description: Abstract 803 Background: Recent findings lend strong support to the contention that histone deacetylase inhibition may be an important epigenetic therapy in the treatment of patients with myeloproliferative neoplasms and emphasize the need to characterize the efficacy and safety of this novel class of cytoreductive agents. Aims: This study was a non-randomized, open-label phase II multicenter study with sixty-three patients (21 essential thrombocythaemia (ET), 42 polycythemia vera (PV)) included from 15 centers. The primary objective was to investigate, if vorinostat as monotherapy in patients with PV and ET was followed by a decline in clonal myeloproliferation as assessed by conventional disease activity parameters. Secondary objectives included assessment of adverse effects during treatment; changes in bone marrow morphology before and after treatment with vorinostat and to investigate whether treatment with vorinostat influences the JAK2 mutant allele burden as assessed by quantitative PCR. (qPCR) Results: Thirty-one patients (49%) were followed to the end of the intervention period. Eighty-one percent of these had a partial (n=20) – or complete (n=5) hematological response according to ELN criteria. Response rates were found to be independent of JAK-status in ET patients. (P=0.83). A tendency towards less favorable responses was observed among patients with 〉 1 previous therapies albeit statistically insignificant (P=0.11). For all but two patients, a clinicohematological response was not followed by a histological remission. The prevalence of splenomegaly was lowered from 48% to 24% (P=0.02). A statistically significant reduction of JAK2 mutant allele burden was observed (P=0.006). No JAK2 positive patients experienced a complete molecular response defined as undetectable JAK2V617F by qPCR. No significant correlation between severity of tumor allele burden at inclusion and a more pronounced molecular response to vorinostat was found using a Spearman correlation analysis (rho = 0.16, p = 0.3). The most commonly reported adverse effects (AEs) during the intervention period among patients who completed the protocol were fatigue and gastrointestinal (anorexia, nausea, vomiting, diarrhea, dryness of the mouth). Gastrointestinal symptoms were generally manageable. Seventy percent of included patients experienced hair loss. Seventeen percent experienced renal toxicity (3 pts. grade I, 1 pt. grade II) and 1 pt. (4%) liver toxicity of unknown grade, which resolved after withdrawal of vorinostat. Forty-three percent of included patients required at least one dose reduction due to AE′s. Forty patients (63 % of patients) discontinued study drug before end of study period due to adverse events (65%), unknown (17.5%), withdrawal of consent (7.5%), no response (2.5%), or progression to acute leukemia (7.5%). Response rates for patients who discontinued therapy, however, showed that approximately 50% of patients who discontinued experienced a clinicohematological response providing evidence that toxicity issues were of concern rather than lack of clinical effect. Conclusions: Vorinostat is effective in patients with ET and PV normalizing elevated leukocyte and platelet counts as well as providing a statistically significant reduction of the JAK2 mutant allele burden and splenomegaly. However, vorinostat was associated with a high dropout rate. Considering the heterogeneity and complexity of oncogenic events, involving both deregulated tyrosine kinase activity as well as epigenetic deregulation in MPN-pathogenesis combination therapy (eg. JAK1-2 inhibitors, DNA-hypomethylating agents, interferon-alpha2) may be more efficacious than single agent therapy. This strategy might also allow for dose reduction of single agents and accordingly a decrease in toxicity, which was the major limiting factor for patients adhering to treatment in the present study. Disclosures: No relevant conflicts of interest to declare.