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Introduction. The study of dialysis patients not needing erythropoiesis-stimulating agents (ESA) for long periods of time has gained interest lately. The aim of this study was to compare laboratory and clinical parameters in hemodialysis patients with autosomal dominant polycystic kidney disease (ADPKD) treated or not with ESA. Methods. Forty-six hemodialysis ADPKD patients were studied for 8 months and they were divided into: group 1- 29 patients who received ESA during the study period and group 2- 17 patients with no ESA treatment. The following parameters were determined: weekly treatment time, body mass index (BMI), pre-session diastolic blood pressure (DBP), pre-session systolic blood pressure (SBP), blood volume processed (BVD), interdialytic body weight gain (IBWG), spKt/V -K/DOQI formula (Kt/V), urea distribution volume (UDV), hemoglobin (Hb), ferritin, transferrin saturation (TSAT), serum phosphate, total serum calcium, normalized protein catabolic ratio (nPCR), albumin, and intact parathormone (PTH). Results. Patients not requiring ESA were more likely to be men, had higher Hb, albumin, total serum calcium levels, IBWG, UDV, BVP, and weekly treatment time. They had lower ferritin, TSAT, SBP. There was no difference regarding DBP, BMI, serum phosphate, PTH, Kt/V, and nPCR. Conclusion. Hemodialysis ADPKD patients not treated with ESA seem to be better nourished, with a slightly better SBP control, with longer dialysis time and increased Hb (despite lower iron loading markers), compared to hemodialysis ADPKD patients treated with ESA.

In the past decade, there has been significant progress in clinical hematology with the discovery of targeted molecules and thus the achievement of both hematologic and molecular responses. Nevertheless, chemotherapy remains the treatment of choice for many types of hematological malignancies. Aggressive chemotherapy leads to immunosuppression, accompanied by a high rate of infections and an increased rate of treatment-related mortality. Invasive fungal infections as well as more common bacterial and viral infections are frequent in immunocompromised patients as they are difficult to diagnose and treat. Pleuropulmonary infections in immunocompromised patients are diagnosed using clinical examination, imaging and laboratory tests. Many laboratory tests are run for several days before a final result is given and are expensive. Computer tomography is a reliable technique, but it is encumbered by high irradiation and high cost, and can assess lesions larger than 1 cm. Transthoracic ultrasound is a modern method, used in the diagnostic algorithm of pleuropulmonary pathology. It allows the diagnosis of small lesions, can be performed at the patients’ bedside, with acceptable costs and no irradiation. A fast, informed and accurate medical decision is essential for a favorable outcome in immunosuppressed patients with an adjacent infection. In the current case series we present the implementation of a new protocol for the follow-up of immunocompromised patients using transthoracic ultrasonography, of great potential use in the clinic.

Polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) represent typical myeloproliferative neoplasms (MPN), usually characterized by specific somatic driver mutations (JAK2 V617F, CALR and MPL). JAK2 46/1 haplotype and telomerase reverse transcriptase gene (TERT) rs2736100 A>C single nucleotide polymorphism (SNP) could represent a large fraction of the genetic predisposition seen in MPN. The rs10974944 C>G SNP, tagging the JAK2 46/1 haplotype, and the TERT rs2736100 A>C SNP were genotyped in 529 MPN patients with known JAK2 V617F, CALR and MPL status, and 433 controls. JAK2 46/1 haplotype strongly correlated to JAK2 V617F-positive MPN and, to a lesser extent, CALR-positive MPN. The TERT rs2736100 A>C SNP strongly correlated to all MPN, regardless of the phenotype (PV, ET or PMF) and major molecular subtype (JAK2 V617F- or CALR-positive). While both variants have a significant contribution, they have nuanced consequences, with JAK2 46/1 predisposing essentially to JAK2 V617F-positive MPN, and TERT rs2736100 A>C having a more general, non-specific effect on all MPN, regardless of phenotype or major molecular subtype.

The study objective was to examine the clinical and hematological significance of receptor CX3CR1 and megakaryocytes in patients with aplastic anemia. Method. 40 patients diagnosed with aplastic anemia and 10 case-control were included in the study. Were analyzed bone-marrow biopsies regarding cellularity, the presence of megakaryocytes and immunohistochemical expression of CX3CR1, CD4, CD8, CD45RO. We divided patients according to CX3CR1 intensity and the presence of megakaryocytes in 4 groups, which were analyzed comparatively. We realized the second division of patients in 4 groups, depending on the CX3CR1 intensity and cellularity of bone-marrow biopsy. Results. Statistically significant differences between the case group and the control group were observed in terms of the percentage of CD8, CD45RO positive cells and positivity for CX3CR1. In the lot of patients with aplastic anemia, we found statistically significant differences between groups with megakaryocytes present and absent, in terms of the number of lymphocytes, platelets, hemoglobin, ESR at 1 hour, ESR at 2 hours, bone marrow cellularity. Conclusions. CX3CR1 could be involved in the pathogenesis of aplastic anemia, influencing bone marrow cellularity. Megakaryocytes influence more hematological parameters, so we suggest using thrombopoietin receptor analogues as 1st line treatment along with the immunosuppressive treatment.

PURPOSE: The ENEST1st sub-analysis presents data based on Philadelphia chromosome (Ph) status, i.e., Ph+ and Ph-/BCR-ABL1 + chronic myeloid leukemia.METHODS: Patients received nilotinib 300 mg twice daily, up to 24 months.RESULTS: At screening, 983 patients were identified as Ph+ and 30 patients as Ph-/BCR-ABL + based on cytogenetic and RT-PCR assessment; 76 patients had unknown karyotype (excluded from this sub-analysis). In the Ph-/BCR-ABL1 + subgroup, no additional chromosomal aberrations were reported. In the Ph+ subgroup, 952 patients had safety and molecular assessments. In the Ph-/BCR-ABL1 + subgroup, 30 patients had safety assessments and 28 were followed up for molecular assessments. At 18 months, the molecular response (MR) 4 rate [MR4; BCR-ABL1 ≤0.01% on International Scale (IS)] was similar in the Ph-/BCR-ABL1+ (39.3%) and Ph+ subgroups (38.1%). By 24 months, the cumulative rates of major molecular response (BCR-ABL1IS≤0.1%;), MR4, and MR4.5(BCR-ABL1IS≤0.0032%) were 85.7, 60.7, and 50.0%, respectively, in the Ph-/BCR-ABL1 + subgroup, and 80.3, 54.7, and 38.3%, respectively, in the Ph+ subgroup. In both Ph-/BCR-ABL1 + and Ph+ subgroups, rash (20 and 22%), pruritus (16.7 and 16.7%), nasopharyngitis (13.3 and 10.4%), fatigue (10 and 14.2%), headache (10 and 15.8%), and nausea (6.7 vs 11.4%) were frequent non-hematologic adverse events, whereas hypophosphatemia (23.3 and 6.8%), anemia (10 and 6.5%), and thrombocytopenia (3.3 and 10.2%) were the common hematologic/biochemical laboratory events.CONCLUSION: Based on similar molecular response and safety results in both subgroups, we conclude that Ph-/BCR-ABL1 + patients benefit from nilotinib in the same way as Ph+ patients.

Backgroud and aims: Castleman’s disease is a rare disorder situated at the boundary between reactive and neoplastic conditions. The pathogenesis is a subject of debate and the limited number of cases renders the study of the disease difficult. In our paper we present a series of six case of Castleman disease with emphasis on clinical presentation, pathology examination and the use of immunohistochemistry in the final diagnosis of the cases. Patients and method: Classification of the disease was based on clinical, imaging and pathological assesment. Specimens were obtained by surgical excission and were routinely processed for the pathology examination. Results: All cases were unicentric disease. Two cases were locally extensive. The clinical symptoms were related mostly to compression effects. Five case were of the hyaline-vascular type and one was included in the plasma cell variant. One case showed angiomyoid differentiation. Discussion: The histological aspect is highly sugestive of a chronic reactive process although some authors include the disease in the lymphproliferative disorders category. Chronic viral stimulation, especially Herpes virus 8 (HHV-8, Kaposi sarcoma virus) infection, the IL-6 signaling cascade, angiogenesis and clonal rearangements play a role in the pathogensis of CD. Conclusions: We strongly belive that by understanding the pathogenesis of the precursor lessions we will gain better understanding of the pathways that lead to neoplasia and that Castleman disesase is a very interesting „natural experiment” ilustrating the progression from chronic antigen stimulation to reactive lymphoid hyperplasia and finally to overt lymphoid neoplasia.

De la introducerea inhibitorului de tirozinkinază (ITK) imatinib mesylate (IM) în terapia leucemiei mieloide cronice (LMC), s-a obsen’at o îmbunătăţire dramatică a răspunsului hematologic, citogenetic şi molecular. Din păcate, la o parte din pacienţi, a apărut şi rezistenţa la ITK, în special datorată mutaţiilor punctiforme ale kinazei ABL, dintre care mutaţia T3151 conferă rezistenţă la toţi cei 3 ITK disponibili în prezent (imatinib, dasatinib, nilotinib). Am efectuat un studiu prospectiv pe un lot de 74 pacienţi diagnosticaţi cu LMC fază cronică, la care am urmărit apariţia mutaţiei T315I. Analiza mutaţională a fost efectuată utilizând tehnica ARMS-PCR, (confimată prin secvenţiere directă în caz de pozitivitate) la interval regulat de 6 luni sau în condiţii de lipsă de răspuns la tratament, de pierdere a răspunsului sau în caz de evoluţie a bolii. Am urmărit corelaţii între prezenţa mutaţiei, caracteristici ale bolii şi răspunsul la tratament, precum şi supravieţuirea la aceşti paci- enţi. Am efectuat o analiză comparativă între pacienţii cu mutaţie T315I şi cei fără mutaţie. Urmărirea pacienţi- lor şi evaluarea răspunsului s-au făcut conform criteriilor European Leukemia Net (ELN). Mutaţia T315I a fost decelată la 3 pacienţi (4.05%) prezenţa ei corelându-se cu vârsta tânără la debut, cu utilizarea a două linii de ITK, cu boala progresivă şi supravieţuire de scurtă durată de la apariţia mutaţiei. Tehnica ARMS-PCR este o metodă sensibilă, uşor de utilizat în detectarea mutaţiei T315I la pacienţii cu LMC fază cronică.

The Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) study included 1089 patients with newly diagnosed chronic myeloid leukemia in chronic phase. The rate of deep molecular response (MR4 (BCR-ABL1less than or equal to0.01% on the International Scale or undetectable BCR-ABL1 with greater than or equal to10?000 ABL1 transcripts)) at 18 months was evaluated as the primary end point, with molecular responses monitored by the European Treatment and Outcome Study network of standardized laboratories. This analysis was conducted after all patients had completed 24 months of study treatment (80.9% of patients) or discontinued early. In patients with typical BCR-ABL1 transcripts and less than or equal to3 months of prior imatinib therapy, 38.4% (404/1052) achieved MR4 at 18 months. Six patients (0.6%) developed accelerated or blastic phase, and 13 (1.2%) died. The safety profile of nilotinib was consistent with that of previous studies, although the frequencies of some nilotinib-associated adverse events were lower (for example, rash, 21.4%). Ischemic cardiovascular events occurred in 6.0% of patients. Routine monitoring of lipid and glucose levels was not mandated in the protocol. These results support the use of frontline nilotinib, particularly when achievement of a deep molecular response (a prerequisite for attempting treatment-free remission in clinical trials) is a treatment goal.

International audience; Intensive treatments like autologous blood stem cell transplantations are standard consolidation treatments for lymphoma and myeloma in young people. The upper age limit for these procedures is constantly increasing. Instead of studying the impact of aging on harvesting peripheral blood stem cells (PBSC), we performed a retrospective study to explore the feasibility of collecting stem cells from patients older than 65 years and compared the efficacy to harvest in younger patients. During a period of 7 years, we identified 108 patients with myeloma or lymphoma who were older than 65 years who underwent PBSC collection. Only eight patients failed to produce a successful harvest. The majority of patients only needed one apheresis (71%). There was a median number of 5.3 x 10(6) CD34+ cells/kg. Our study demonstrated that older patients can also undergo PBSC harvests similar to younger patients.

According to recent epidemiological studies, malignant diseases represent the second cause of mortality worldwide and metastasis is the main cause of morbidity and mortality in most cancers. Even if the concept of "cancer stem cells" (CSCs) was anticipated by the genius of Rudolph Virchow, the father of modern pathology, more than 150 years ago, it is only in last few years that that scientists have begun to develop strategies aimed at inhibiting CSCs at a molecular level, the only way cancer can truly be attacked, by crossing the border between histology and molecular biology. The current concise review aims at emphasizing the main characteristics of tumor initiating cells, bridging the basic science to clinical hematology and oncology.

Chronic lymphocytic leukemia (CLL) has a heterogeneous clinical course. Among useful markers in identifiyng patients with poor outcome are unmutated IgVH, ZAP-70 and CD38 expression. Both ZAP-70 and CD38 were shown to be capable of identifying aggressive CLL.We analysed data from 35 patients diagnosed with CLL based on morphological and immunophenotypical criteria. In all cases peripheral blood immunophenotyping was performed as initial diagnostic test. Immunohistochemical expression of ZAP-70 and CD38 was evaluated on 21 cases of lymph node biopsies and 14 cases of bone marrow biopsies, performed at the time of diagnosis. In addition in-situ hybridization for EBER-1 was evaluated.The median age of patients was 60 years and we noted a slight male predominance. The immunophenotypic criteria (C23Prognostic information given by ZAP-70 and CD38 could be used in guiding treatment decisions and they probably should be recommended to all patients with B-CLL in trying to obtain a more clear profile of the disease at the time of diagnosis.

Background: The cytogenetic hallmark of chronic myeloid leukemia (CML) is a translocation, t(9;22)(q34;q11), resulting in the Philadelphia (Ph) or derivative 22 chromosome. Cytogenetic studies indicate that 90-95% of cases have the Ph chromosome or recognized variant (Ph+ CML), with the remaining 5-10% having a normal or near normal karyotype despite the presence of the BCR-ABL fusion (Ph-negative, BCR-ABL-positive CML). Tyrosine kinase inhibitors (TKIs) have been approved for the treatment of patients with Ph+ CML. The effect of TKIs in patients with Ph- CML has not been described in detail. Objective: ENEST1st (Evaluating Nilotinib Efficacy and Safety in clinical Trials as First-Line Treatment) sub-group analysis was planned to explore the effect of nilotinib in patients with Ph- CML. Patients and Methods: ENEST1st (NCT01061177) is a phase 3b, multicenter, open-label study of nilotinib 300 mg twice daily (BID) in adults with newly diagnosed BCR-ABL+ CML-CP. Patients with confirmed Ph- CML-CP were included in the sub-analysis. Primary endpoint was rate of MR4 (defined as BCR-ABL ≤ 0.01% on the International Scale [BCR-ABLIS] or undetectable BCR-ABL in cDNA with ≥ 10,000 ABL transcripts) at 18 mo. Results: Of the 1089 patients included in ENEST1st study, 30 patients (2.7%) were Ph- (only one of those had a cytogenetic aberration [del9q34]), 983 patients (90.3%) were Ph+ and 76 (7.0%) patients had an unknown karyotype at baseline. Among these patients, 28 pts (2.7%) Ph- and 952 pts (90.5%) Ph + with b2a2 and/or b3a2 BCR-ABL transcripts and treated with imatinib for ≤ 3 mo were analyzed for molecular response (MR). Median age of patients with Ph- CML was 51.5 years (range, 21.0 to 75.0). EUTOS score was low in 86.7% and high in 6.7% of patients (6.7% missing). Sokal risk score was low, intermediate, and high in 33.3%, 30.0%, and 23.3% of patients, respectively (13.3% missing). In Ph+ CML patients, the median age was 53.0 years (range, 18.0 to 91.0). EUTOS score was low in 82.0% and high in 9.2% of pts (8.9% missing). Sokal risk score was low, intermediate, and high in 34.8%, 37.2%, and 18.1% of pts, respectively (9.9% missing). The MR4 rate at 18 mo in Ph- population was 39.3% (95% CI, 21.2% - 57.4%). The cumulative incidence of MR4 by18 mo was60.7% (95% CI, 42.6% - 78.8%). Rates of cumulative MMR (BCR-ABLIS ≤0.1%) and MR4.5 (BCR-ABLIS ≤0.0032%) by 18 mo were 85.7% (95% CI, 72.8% - 98.7%) and 46.4% (95% CI, 28.0% - 64.9%), respectively. For the Ph+ CML population, the MR4 rate at 18 mo was 38.1% (95% CI, 35.0% - 41.2%). The cumulative incidence of MR4 by 18 mo was48.1% (95% CI, 44.9% - 51.3%). Rates of cumulative MMR (BCR-ABLIS ≤0.1%) and MR4.5 (BCR-ABLIS ≤0.0032%) by 18 mo were 76.8% (95% CI, 74.1% - 79.5%) and 31.4% (95% CI, 28.5% - 34.4%), respectively. Rates of MMR, MR4, and MR4.5 at 18 and 24 mo among Ph- population and the Ph+ CML population are summarized in the Table. The 3-month BCR-ABL level has been shown to be predictive of MR in the Ph+ CML population. Among Ph- population not pretreated with imatinib (n = 14), 85.7% achieved BCR-ABLIS ≤ 1%, no patients had BCR-ABLIS > 1% to ≤ 10% and > 10% at 3 mo. Two patients did not have the assessment at 3 mo. Among patients with Ph+ CML not pretreated with imatinib (n = 802), 70.0% , 17.0%, and 2.7% of patients achieved BCR-ABLIS ≤ 1% , > 1% to ≤ 10%, and >10% respectively. Eighty-five patients did not have the assessment at 3 mo. Most common AEs experienced by the Ph- population were hypophosphatemia (25%), rash (18%), pruritus (14%), nasopharyngitis (14%), alanine aminotransferase increase (14%), and blood bilirubin increase (14%). In the Ph+ population, the list of most common AEs includes rash (22%), pruritus (17%), headache (16%), and fatigue (14%). Conclusions: The MR rates observed in Ph- CML subgroup are similar to the rates observed in Ph+ CML patients. These results indicate that nilotinib is active in this previously unexplored population as well and larger studies should be conducted to confirm the results. The safety results observed in Ph-CML patients are similar to the ones observed in the Ph+ CML pts. aCML patients with typical b2a2 and/or b3a2 BCR-ABL transcripts and ≤3 mo of prior imatinib Figure 1. Figure 1. Disclosures Hochhaus: ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mahon:Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Coriu:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ossenkoppele:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Cross:Ariad: Consultancy, Honoraria, Research Funding; Qiagen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Müller:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Rea:Pfizer: Honoraria; Ariad: Honoraria; BMS: Honoraria; Novartis: Honoraria. Steegmann:Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Research Funding. Castagnetti:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. Hellmann:Novartis: Research Funding; BMS: Research Funding. Rosti:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau. Gattermann:Novartis: Honoraria, Research Funding. Gutierrez:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; PFIZER: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tubazio:Novartis: Employment. Pellegrino:Novartis: Employment. Dezzani:Novartis: Employment. Giles:Novartis: Consultancy, Honoraria, Research Funding.

[Graphic][1] Background : The incidence of CML increases with age and also the disease characteristics vary with age. However, whether age has any impact on molecular response (MR) with TKIs or not has not been clearly established. Objective: To assess the effect of age on MR and adverse events (AEs) with nilotinib (NIL) in patients (pts) with CML in the ENEST1st ([NCT01061177][2]) phase 3b trial. Patients and Methods: ENEST1st is an open-label study of NIL 300 mg BID in adults with newly diagnosed CML-CP. Treated pts with typical transcripts and ≤ 3 months of prior imatinib (IM) therapy were included in the sub-analysis and were stratified according to age (> 65 years and ≤ 65 years). Primary endpoint was rate of MR4 (defined as BCR-ABL ≤ 0.01% on the International Scale [BCR-ABLIS ] or undetectable BCR-ABL in cDNA with ≥ 10,000 ABL transcripts) at 18 months. Results: Of the 1089 pts (median age, 53 years; range, 18 - 91 years) enrolled into the study, 1052 had b2a2 and/or b3a2 BCR-ABL transcripts and were treated with IM for ≤ 3 months. Sokal risk scores were low, intermediate, and high in 34.9%, 37.5%, and 18.1% of pts, respectively (9.5% missing). The rate of MR4 at 18 months in all treated pts with typical transcripts and ≤ 3 months of prior IM (n = 1052) was 38.4% (95% CI, 35.5% - 41.3%). The cumulative rates of MR at 24 months are shown in the figure. At 12 months the rates of MR4 and MR4.5 were 30.8% and 15.3% respectively. Among pts who were in MR4 and MR4.5 at 12 months, 60.8% and 33.9% pts were able to maintain continuous MR4 and MR4.5 until Month 24, with no documented loss of MR4 and MR4.5 between 12 and 24 months, respectively. Among all pts treated (n=1089), six pts (0.6%) progressed to accelerated phase/blast crisis (AP/BC) on study; 13 pts (1.2%) died by 24 months, including one due to CML progression (16 month after study drug discontinuation). The most common AEs of any cause were rash (21.4%), pruritus (16.5%), and headache (15.2%). Subgroup-analysis by age: As per the WHO guidelines, pts > 65 years are defined as older. Accordingly, for this sub-analysis, pts with typical transcripts and treated with IM for ≤ 3 months (n = 1052) were stratified into two subgroups: 851 pts (80.9%) were ≤ 65 years of age and 201 pts (19.1%) were > 65 years old at the time of enrollment. The median age at enrollment was 71 (range 66 - 91) and 48 (range 18 - 65) years in the old and young group, respectively. Among old pts, Sokal risk scores were low, intermediate, and high in 4.5%, 61.2%, and 23.4% of pts, respectively (10.9% missing). Among young pts, Sokal risk scores were low, intermediate, and high in 42.1%, 32.0%, and 16.9% of pts, respectively (9.0% missing). Cumulative incidence of MR4 by 18 months was 48.8% (95% CI, 45.4% - 52.1%) among younger pts and 48.3% (95% CI, 41.4% - 55.2%) in older pts. Rate of MR4 by 18 months among younger pts with low, intermediate, and high Sokal score was 53.6%, 45.2%, and 35.4%, respectively. Rate of MR4 by 18 months among older pts with low, intermediate, and high Sokal score was 44.4%, 49.6%, and 44.7%, respectively. The incidence rate of MR4.5 by 18 months in younger pts and older pts was 32.5% and 28.4%, respectively. Most common AEs experienced by younger patients were rash (23%), headache (17%), pruritus (16%), and fatigue (14%). In older population, the list of most common AEs includes pruritus (19%), nausea (18%), and rash (14%) (Table). Conclusions : In this study, frontline NIL yielded equivalent rates of molecular responses in older and younger pts with a similar safety profile. | Adverse Event | Patients ≤65 years (n = 851) % | Patients >65 years (n = 201) % | | ---------------- | ------------------------------------- | ------------------------------------- | | Rash | 23.2 | 13.8 | | Headache | 17.1 | 7.6 | | Pruritus | 16.0 | 18.6 | | Fatigue | 14.0 | 13.3 | | Thrombocytopenia | 11.0 | 7.6 | | Nasopharyngitis | 10.8 | 8.6 | | Alopecia | 10.8 | 9.5 | | Nausea | 9.8 | 17.6 | | Diarrhea | 8.0 | 11.4 | | Asthenia | 8.4 | 11.0 | | Anemia | 5.1 | 10.5 | | Abdominal pain | 6.9 | 10.5 | | Dry skin | 8.2 | 10.0 | Table. ![Figure 1.][3] Figure 1. Disclosures Giles: Novartis: Consultancy, Honoraria, Research Funding. Rea: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Baccarani: NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cross: Ariad: Consultancy, Honoraria, Research Funding; Qiagen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Steegmann: Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Griskevicius: Novartis: Honoraria, Research Funding. Coriu: PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ossenkoppele: Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Mahon: Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Muller: Ariad: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Hellmann: BMS: Research Funding; Novartis: Research Funding. Porkka: Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Brummendorf: Novartis: Consultancy, Patents & Royalties, Research Funding. Gastl: AOP Orphan: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Tubazio: Novartis: Employment. Pellegrino: Novartis: Employment. Dezzani: Novartis: Employment. Rosti: Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Hochhaus: Novartis: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. [1]: /embed/inline-graphic-2.gif [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01061177&atom=%2Fbloodjournal%2F126%2F23%2F479.atom [3]: pending:yes

Background Nilotinib is a selective BCR-ABL tyrosine kinase inhibitor (TKI) that has been shown to be more active than imatinib at inducing earlier and deeper molecular responses in the frontline treatment of chronic myeloid leukemia (CML; Larson, et al. Leukemia. 2012). ENEST1st (Evaluating Nilotinib Efficacy and Safety in clinical Trials as First-Line Treatment, NCT01061177) is the largest study ever in TKI-treated patients (pts) with CML. Its primary endpoint was the rate of MR4 (defined as BCR-ABL ≤ 0.01% on the International Scale [BCR-ABLIS] or undetectable BCR-ABL in cDNA with ≥ 10,000 ABL transcripts) at 18 mo. Molecular response (MR) was assessed by standardized quantitative polymerase chain reaction (RQ-PCR) in the 14-laboratory network of the European Treatment and Outcomes Study (EUTOS). Methods ENEST1st is a phase 3b, open-label study of nilotinib 300 mg twice daily (BID) in adults with newly diagnosed BCR-ABL-positive CML in chronic phase. MR was assessed every 3 mo by peripheral blood RQ-PCR at 1 of 14 EUTOS laboratories. Following completion of the 18-mo primary efficacy time point, all pts continued to receive treatment and were followed for an additional 6 mo. Results 1160 pts were screened, with 1086 eligible pts treated in 26 European countries. Overall, median age was 53 y (range, 18-91 y); 59.2% of pts were male, 96.9% had typical b2a2 and/or b3a2 BCR-ABL transcripts (intent-to-treat population for MR analyses), and 90.3% were Philadelphia chromosome–positive by bone marrow metaphase cytogenetics. Per protocol, efficacy and safety analyses were conducted in the initial 819 pts (75.4% of enrolled pts) who were on study for 24 mo or discontinued early. In this group, median age was 53 y (range, 18-91 y), and 58.5% were male; Sokal risk scores were low, intermediate, and high in 33.7%, 39.5%, and 18.7% of pts, respectively (8.1% missing). EUTOS scores were low in 83.8% and high in 9.2% of pts (7.0% missing). A total of 658 pts (80.3%) completed 24 mo of treatment; 161 pts (19.7%) discontinued early. The most common reasons for discontinuation included adverse events (AEs; 10.5%), withdrawal of consent (2.7%), and disease progression (as indicated by the investigator; 1.7%). MR4 rate at 18 mo was 43.0% (95% CI, 39.3-46.8). Rates of major MR (MMR, BCR-ABLIS ≤ 0.1%), MR4, and MR4.5 (BCR-ABLIS ≤ 0.0032% or undetectable cDNA with ≥ 32,000 ABL transcripts) at 18 and 24 mo are shown in the Table. Cumulative incidence of MR4 by 18 mo was 50.1%. All pts were followed up for progression or death for 24 months after start of treatment: 7 pts (0.85%) experienced progression to accelerated phase/blast crisis (AP/BC) while on core treatment or after discontinuation. Overall, 12 pts (1.5%) died; 2 of them died following progression to AP/BC. The safety profile of nilotinib was similar to that observed in other frontline studies. The most common AEs of any relationship were rash (21.4%), pruritus (16.8%), and headache (15.0%); most AEs were grade 1-2. Rates of grade 3-4 hematological AEs were low, with thrombocytopenia and neutropenia reported in 8.2% and 2.9% of pts, respectively. Peripheral arterial occlusive disease (PAOD) occurred in 13 pts (1.6%), ischemic heart disease in 31 (3.8%), and ischemic cerebrovascular conditions in 4 (0.5%). Three cases of pain in extremities are under investigation for potential relationship to PAOD. Conclusions ENEST1st confirms that frontline nilotinib results in high rates of deeper and earlier MR and very low rates of progression to AP/BC. By 18 mo, half of pts achieved a response of MR4. This MR4 rate supports the use of frontline nilotinib as a treatment of choice on which to develop treatment-free remission studies. Finally, the molecular response rates measured in a standardized and validated network of 14 EUTOS laboratories in ENEST1st provide prospective confirmation of the centrally reviewed molecular response rates reported in the ENESTnd trial. Disclosures: Giles: Novartis: Consultancy, Research Funding. Baccarani:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Ariad: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Brümmendorf:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy. Mahon:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Brisol Myers Squibb: Consultancy, Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Rosti:Novartis: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau. Saglio:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Steegmann:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ossenkoppele:Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau. Echeveste:Celgene: Consultancy; Novartis: Consultancy. Gattermann:Novartis: Honoraria, Research Funding, Speakers Bureau. Griskevicius:Novartis: Consultancy, Research Funding. le Coutre:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria. Masszi:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Rea:Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Richter:Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau. 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. Tulliez:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Schuld:Novartis: Employment, Equity Ownership. Pellegrino:Novartis: Employment. Walasek:Novartis: Employment. Cross:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria. Hochhaus:Novartis: Research Funding; Bristol Myers Squibb: Research Funding; Ariad: Research Funding; Pfizer: Research Funding.

PURPOSE: Achievement of deep molecular response with a tyrosine kinase inhibitor in patients with chronic myeloid leukemia (CML) is required to attempt discontinuation of therapy in these patients. The current subanalysis from the Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) study evaluated whether age has an impact on the achievement of deeper molecular responses or safety with frontline nilotinib in patients with CML.METHODS: ENEST1st is an open-label, multicenter, single-arm, prospective study of nilotinib 300 mg twice daily in patients with newly diagnosed CML in chronic phase. The patients were stratified into the following 4 groups based on age: young (18-39 years), middle age (40-59 years), elderly (60-74 years), and old (≥75 years). The primary end point was the rate of molecular response 4 ([MR4] BCR-ABL1 ≤0.01% on the international scale) at 18 months from the initiation of nilotinib.RESULTS: Of the 1091 patients enrolled, 1089 were considered in the analysis, of whom, 23% (n = 243), 45% (n = 494), 27% (n = 300), and 5% (n = 52) were categorized as young, middle age, elderly, and old, respectively. At 18 months, the rates of MR4were 33.9% (95% confidence interval [CI], 27.8-40.0%) in the young, 39.6% (95% CI, 35.3-44.0%) in the middle-aged, 40.5% (95% CI, 34.8-46.1%) in the elderly, and 35.4% (95% CI, 21.9-48.9%) in the old patients. Although the incidence of adverse events was slightly different, no new specific safety signals were observed across the 4 age groups.CONCLUSIONS: This subanalysis of the ENEST1st study showed that age did not have a relevant impact on the deep molecular response rates associated with nilotinib therapy in newly diagnosed patients with CML and eventually on the eligibility of the patients to attempt treatment discontinuation.