Search

© Springer Science+Business Media, LLC, part of Springer Nature 2018, Chemotherapy-induced cardiotoxicity is a growing concern. The cardiotoxic impact of new drugs such as tyrosine kinase inhibitors is unknown, especially the ones used for chronic myeloid leukemia. We aim to evaluate nilotinib- and imatinib-induced cardiotoxicity. Single-center prospective study of consecutive patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors was conducted during 2015. Patients underwent an initial clinical, laboratorial and echocardiographic evaluation, repeated after 1 year. Eleven patients were included [60.0 (11) years, 63.6% of males; seven patients treated with imatinib and four with nilotinib]. After 1 year of follow-up, all patients remained in functional NYHA class I, with a similar Minnesota quality of life score. Also there was no difference in the biomarkers evaluated (cystatin-C and NT-proBNP). Likewise, no modification in systolic or diastolic function evaluated by echocardiography was observed. All patients presented normal values of longitudinal, circumferential and radial strain in the baseline study, without changes during follow-up. In addition, there were no differences between the two tyrosine kinase inhibitors used, considering all the aforementioned variables. No clinical, laboratory or echocardiographic evidence of nilotinib- and imatinib-induced cardiotoxicity was observed. However, these results should be confirmed in multicenter studies given the low incidence of chronic myeloid leukemia.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017.

Sweet syndrome (SS) is a neutrophilic dermatosis that may be associated with malignancies, especially hematological. We describe the case of a 53-year-old woman with a clinical presentation suggestive of SS, accompanied by pancytopenia and a hypercellular marrow with signs of myelodysplasia. The histopathological findings were characterized as an SS-like cutaneous neutrophilic infiltrate with atypical myeloid cells, myeloperoxidase, and BCR-ABL+, which were absent in peripheral blood and bone marrow aspirate. The patient was treated with systemic corticosteroids with resolution of symptoms and relapse 3 months later when we tried drug withdrawal. Eight months later, the patient was admitted to hematology for a mature acute myelogenous leukemia with an FLT3 mutation. The patient successfully underwent medullar allotransplant and is now asymptomatic (5-month follow-up). This case describes a patient with an acute myelogenous leukemia presenting initially with heralding SS-like cutaneous neutrophilic infiltrate with atypical BCR-ABL+ myeloid cells, as a form of aleukemia cutis. Early recognition of this so-called aleukemic leukemia cutis may allow clinicians to intervene earlier, initiating effective treatment.

Hypereosinophilic syndromes are characterized by sustained overproduction of eosinophils, leading to eosinophilic infiltration, mediator release and multi-organ damage.A 67 year old male was referred to our Department for investigation of a persistent mild-to-moderate eosinophilia, identified 10 years previously and unresponsive to corticosteroid treatment. No other alterations were present in his differential blood count and physical examination was unremarkable. Allergic, rheumatologic and iatrogenic causes of eosinophilia were excluded by clinical history, skin-prick tests and blood and stool analysis. Iliac crest bone marrow aspiration and biopsy were performed, revealing normal cellularity with an increased eosinophil count (6%). RT-PCR of the aspirate revealed the presence of transcripts of ETV6/PDGFR-beta t(5;12) gene fusion. Karyotype analysis was normal and no mutation in PDFGR-alpha was identified. There was no evidence in analytic or imaging studies of cardiac, skin, neurologic, pulmonary or splenic involvement. A skin biopsy showed no evidence of pathologic infiltration. Initially the patient was treated with a 100 mg daily dose of imatinib mesylate, a specific inhibitor of the tyrosine-kinase domain of PDGFR. Subsequently, the daily dosage was increased to 200 mg/day to obtain eosinophil count normalization. Currently, he is under monthly hematologic and hepatic function screening. No drug side effects have been reported.This patient was diagnosed with a rare myeloproliferative variant of hypereosinophilic syndrome due to a t(5;12) ETV6/PDGFR-beta translocation. Imatinib mesylate, previously used successfully in syndromes associated with PDFGR-alpha mutations, showed efficacy in the context of this mutation as well.

Chronic Myeloid Leukemia (CML) is a clonal stem cell disease characterized by the expression of the fusion protein bcr-abl1, which has deregulated tirosine-kinase activity. Tyrosine kinase inhibitors (TKIs), and in particular imatinib, introduced fundamental changes in the treatment of CML, becoming, in most cases, the first-line treatment of choice in the chronic phase of this disease. Compared to other available therapies imatinib results in a marked increase in overall survival, tolerability and quality of life. The introduction of second generation TKI, with increased potency against bcr-abl1, expanded the number of therapeutic options for this disease and offers an alternative for patients resistant or intolerant to imatinib or who have progressed to the accelerated phase under this therapy. In order to achieve optimal outcomes, TKI therapy must be managed rigorously, requiring a careful monitoring of treatment response in pre-established time periods, thus permitting disease evaluation and safe decision of the most adequate option. Despite the definition of the criteria for imatinib treatment response, the therapeutic strategies to adopt according to the responses obtained are less clear. The objective of this paper is to review the criteria for CML diagnosis, treatment and monitoring, with recommendations as to the most adequate therapeutic choice according to the response to TKI therapy. The paper also focuses the current lines of investigation and debate areas that in the short term can significantly change the therapeutic scenario in this disease. These recommendations, supported by published scientific evidence and by the clinical practice of the expert panel involved in their elaboration, may constitute an important instrument for a better understanding and standardisation of the treatment and monitoring of CML in Portugal.

Evaluate costs and benefits of rituximab in combination with cyclophosphamide/vincristine/prednisolone chemotherapy regimen (R-CVP), in previously untreated patients with indolent non-Hodgkin lymphoma (NHL), compared to CVP alone from a Portuguese National Health System (NHS) perspective.Cost-effectiveness (Life Years Gained--LYG) and cost-utility analysis (Quality Adjusted Life Years--QALYs) were performed for a time horizon of 10 years, according to a Markov economic model with three health states (progression free survival, progression and death) and monthly cycles for a population of previously untreated patients with indolent NHL. Data from a phase III clinical trial was used and expanded to include unpublished 53-month median follow-up data. Survival after first-line therapy was estimated from the Scotland and Newcastle Lymphoma Group registry data and utilities were derived from a study in the UK performed in patients with follicular lymphoma. Resource consumption was estimated by a Portuguese expert panel (Delbecq Panel). Costs were calculated from the Portuguese NHS perspective through official data with prices updated to 2008. Only direct medical costs were considered. Costs and clinical outcomes were discounted at 5% per annum. Deterministic and probabilistic sensitivity analysis were performed around assumptions on the time horizon, costs, utilities and excess mortality rate due to progression applied in the base-case analysis.The 10-year base-case analysis showed a lower total cost per patient with CVP alone (€ 85,838) in comparison with R-CVP (€ 87,774). Life expectancy and Quality adjusted life expectancy per patient were higher with R-CVP (6.361 and 4.166, respectively) than with CVP alone (5.557 and 3.438, respectively), representing increases of 0.804 in LYG and 0.728 (8.7 months) in QALYs gained. The incremental cost per LYG was € 2,407 and the incremental cost per QALY gained was € 2,661. The probabilistic sensitivity analysis confirmed the robustness of the base-case analysis results.This study demonstrates that the combination R-CVP in previously untreated indolent NHL patients improves life expectancy and is a cost-effective alternative to CVP in Portugal.

separating normal epidermis from a diffuse dermal infiltrate of lymphoid blast cells with round and regular nuclei, inconspicuous nucleoli, and scanty, moderately basophilic cytoplasm. Immunophenotype analysis revealed strong positivity for CD 10.The patient wastreated with methotrexate, teniposide, cytosine arabinoside, and local irradiation, and a second complete remission was induced. In December 1990, while the patient continued to receive maintenance chemotherapy, a nodule appeared in his right leg, adjacent to the previously irradiated field. Again, no other organs or systems were involved. In March 1991 the patient had autologous bone marrow transplantation. The conditioning regimen consisted of busulfan, 16 rug/kg, and melphalan, 180 mg/m2, and a third complete remission was achieved. In January 1992 the patient noticed reappearance of two nodules in the right leg. During the next 2 months more than 100 papules and nodules developed on his chest, back, shoulders, arms, neck, and face (Fig. I). Laboratory findings were unremarkable, and both the bone marrow and cerebrospinal fluid were negative for leukemic cells. The histopathologic findings in the skin Fig. 1. Patient's back shows numerous papules and nodules.

Introduction MM is characterized by the presence of a monoclonal immunoglobulin in the serum and/or urine, produced by malignant plasma cells. MM has a highly uncertain evolution and prognostic depending on age, stage and cytogenetic abnormalities. FLC is a readily available laboratory test and has independent prognostic significance in all the plasma cell disease entities helping to clarify International Staging System (ISS). Its value in the era of new therapeutic drugs is to be proved. Purpose To determine the prognostic value of baseline serum FLCr in patients with newly diagnosed MM, consecutively treated with thalidomide or bortezomib based regimens. Methods This is a retrospective study, from July 2004 to December 2012. We studied the relationship of baseline FLCr with outcome and its contribution to clarify the prognostic value of ISS. Serum FLC levels were measured in frozen sera at initial diagnosis, using a latex-enhanced immunoassay (The Binding Site, Birmingham, UK) on a Beckman Coulter nephelometric analyzer. FLCr was calculated as k/λ (reference range: 0,26-1,65). Abnormal FLCr was defined of < 0,03 or > 32,00 and standard FLCr of 0,03-32. Patients have been staged by ISS and Mayo Clinic stratification. All patients received at least two cycles of a thalidomide based regimen, 91 patients (38,9%): thalidomide, doxorubicin, dexamethasone (TAD), 37 patients (15,8%) and melphalan/cyclophosphamide, thalidomide, prednisone (M/CTP), 54 patients (23,0%) or bortezomib based regimens, 143 patients (61,1%): bortezomib, doxorubicin and dexamethasone (PAD), 53 patients (22,6%), bortezomib, cyclophosphamide and dexamethasone (Cy-Bor-D), 7 patients (2,9%) and melphalan/cyclophosphamide, bortezomib, prednisone (M/CVP), 83 patients (35,6%). Median follow-up from diagnosis was 25 months. Follow-up was through the review of each patient’s complete medical records at our center. Statistical analysis was performed with SPSS 20 ®. Results We reviewed 234 patients consecutively treated. Male gender was 46,6% and median age was 67 years (22-84y). The Ig type was IgG in 59,4%, IgA in 22,2%, IgD in 1,7%, light chains MM in 15,4% and non-secretory MM in 1,3%. The median Hb level was 10,7g/dL (4,9-16,7g/dL) and serum albumin was 27,4 g/L (9,0-50-0g/L). Twenty five percent of patients had a creatinine clearance 32,00) and 49,1% had standard FLCr 0,03-32,00. FISH was performed in 74,4% patients: 26,0% presented high-risk features. Overall survival (OS) and progression free survival (PFS) were significantly different according the patients presented 0, 1, 2 or 3 Mayo Clinic risk factors, with median survival times of 83, not reached (NR), 39 and 36 months, for OS, p=0,000, and 41, 41, 17 and 17 months for PFS, p=0,000. Patients with abnormal FLCr had similar outcome of standard FLCr. Patients in ISS II had significant different OS according the FLCr: 77 and 39 months for standard and abnormal FLCr, respectively, P=0,015. There was no such correlation on stages I and III. Conclusions Baseline serum FLCr associated to others risk-factors like serum β2-microglobuline and albumin is a powerful prognostic factor for survival in newly diagnosed MM treated with thalidomide or bortezomib-based therapies. FLCr helps to clarify the outcome of ISS stage II patients identifying a subgroup with clearly inferior outcome. Disclosures: Esteves: Yassen: Consultancy; Celgene: Consultancy. Raposo:Roche; lymphoproliferative diseases: Consultancy. Guerra:Novartis, Bristol-Myers Squibb and Amgen. Advisory bord meetings. Areas involved: Myeloproliferative neoplasms and acute leukaemia: Consultancy.

Introduction MM is a B cell malignancy characterized by the presence of a monoclonal immunoglobulin (Ig) in the serum and/or urine produced by clonal plasma cells. MM has a variable outcome depending on age, stage and cytogenetic abnormalities. FLCr is a readily available laboratory test and has independent prognostic significance in all the plasma cell disease entities, helping to clarify International Staging System (ISS), namely the heterogeneous stage II. In the era of new therapeutic agents trending to personalized therapy, its prognostic value needs to be proved. Purpose To evaluate the prognostic value of baseline serum FLCr on outcome of patients with newly diagnosed MM eligible for HDM treated with thalidomide or bortezomib based regimens. Methods This is a retrospective study, from January 2005 to December 2012. We analyzed the relationship of baseline FLCr with outcome and its contribution to clarify the prognostic value of ISS. Serum FLC levels were measured in frozen sera drew at diagnosis before treatment, using a latex-enhanced immunoassay (The Binding Site, Birmingham, UK) on a Beckman Coulter nephelometric analyzer. FLCr was calculated as k/λ (reference range: 0,26-1,65). Abnormal FLCr was defined of 32,00 and standard FLCr of 0,03-32. Patients have been staged by ISS and Mayo Clinic stratification. All patients received at least two cycles of a bortezomib based regimen (64,7%), with doxorubicin and dexamethasone (PAD) in 55 patients (53,9%), with cyclophosphamide and dexamethasone (Cy-Bor-D) in 11 patients (10,8%) or thalidomide, doxorubicin and dexamethasone (TAD) in 36 patients (35,3%). Median follow-up from diagnosis was 30 months. Follow-up was through the review of each patient’s complete medical records at our center. Statistical analysis was performed with SPSS 20 ®. Results We reviewed 102 patients treated with thalidomide or bortezomib based-regimens eligible for HDM. Fifty one percent of patients were male and median age was 52 years (22-70y). The Ig type was IgG in 62,7%, IgA in 14,7%, IgD in 3,9%, light chains MM in 17,7% and non-secretory MM in 1,0% of patients. The median Hb level was 9,8 g/dL (5,3-16,7mg/L) and median serum albumin was 31,5 g/L (22,3-48,3g/L). Creatinine clearance 32,00). Cytogenetic FISH analysis was performed in 86,3% of patients: 32,4% presented high-risk features. We observed a significant difference on overall survival (OS) and progression free survival (PFS) according to Mayo Clinic risk-factors: 0, not reached (NR), 1, NR, 2, 49 months and 3, 71 months for OS (P=0,000) and 0, 68 months, 1, 55 months, 2, 16 months and 3, 24 months for PFS (P=0,000). According the FLCr there was a significant advantage on OS for standard FLCr: NR vs 71 months (P=0,035). A trend to a better OS (P=0,061) was observed in stage II patients with standard FLCr but no significant difference at any stage. Conclusions Baseline serum FLCr associated to others risk-factors like serum β2-microglobuline and albumin is a powerful prognostic factor for survival in newly diagnosed MM eligible for HDM treated with thalidomide or bortezomib-based therapies. We fail to fully demonstrate FLCr prognostic value on ISS stage II patients, only a trend for better outcome with standard FLCr. Disclosures: Esteves: Janssen-Cylag and Celgene. Consultancy on the area of multiple myeloma and acute myeloid leukaemia: Consultancy. Raposo:Roche; lymphoproliferative diseases: Consultancy. Guerra:Novartis, Bristol-Myers Squibb and Amgen. Advisory bord meetings. Areas involved: Myeloproliferative neoplasms and acute leukaemia: Consultancy.

Abstract 1689 Background: Approximately half of patients with chronic-phase chronic myelogenous leukemia (CP-CML) fail imatinib treatment, both in interventional (Deininger et al., Blood 2009 114: abstract 1126) and observational trials (Michallet et al., Curr Med Res Opin 2010;26(2): 307–17), primarily due to the development of resistance and/or toxicity (Kantarjian and Cortes. J Clin Oncol 2011; 29(12): 1512–16). Clinical evidence suggests that optimal outcomes are achieved when dasatinib is administered early after imatinib failure (Quintas-Cardama et al., Cancer 2009;115(13): 2912–21); however, limited data are available regarding outcome of patients intolerant to imatinib in the real-life setting. Aims: FORTE (Factors impacting On Response To dasatinib in Europe) is a European observational study that aims to estimate the relationship between time elapsed from first detection of imatinib resistance/intolerance until initiation of dasatinib and best response to dasatinib, adjusted for other potentially explanatory factors. Methods: Data were collected retrospectively and prospectively from medical records. Best response to dasatinib, as recorded in patient's charts, was reported by an ordered categorical variable, combining all types of response achieved by a patient and selecting the “highest” level. A predefined list of covariates (sex; age at dasatinib initiation; time from diagnosis to dasatinib initiation; best response to prior imatinib and last imatinib dose) were entered/removed in a Proportional Odds model to identify factors potentially influencing dasatinib best response over a 12-month observation period. Results presented here focus on the imatinib-intolerant subpopulation. Results: FORTE enrolled 549 adult patients with imatinib-resistant/intolerant CP-CML at 124 sites across 12 European countries. Of 457 eligible patients, 176 (39%) were imatinib intolerant, including 71 (16%) who were both resistant and intolerant to imatinib. Approximately half (47%) of intolerant patients were male. Median age at dasatinib initiation was 59 years and median times from CML diagnosis to imatinib and dasatinib initiation were 1.5 and 39.8 months, respectively. Sokal and Hasford scores were intermediate/high in 74% and 72% of assessed patients, respectively. Overall, 54% of 171 imatinib-intolerant patients had achieved a complete cytogenetic response (CCyR) or major molecular response (MMR) on imatinib. During the 12 month observation period, 72% of imatinib-intolerant patients achieved a CCyR or MMR with dasatinib. Adjusting for the effect of best imatinib response, an analysis of 161 evaluable patients showed strong statistical evidence (p Conclusions: Results from the imatinib-intolerant population of the FORTE study suggest that an early switch to dasatinib provides a clinical advantage to CP-CML patients intolerant to imatinib. Findings from this real-life observation are consistent with data from interventional trials. Disclosures: Marin: Bristol-Myers Squibb: Research Funding. Morra:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Janssen Cilag: Speakers Bureau. Niederwieser:Bristol-Myers Squibb: Speakers Bureau. Schloegl:AOP Orphan: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Ho:Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Ossenkoppele:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Guerra: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. Mori:Bristol-Myers Squibb: Employment. Pans:Bristol-Myers Squibb: Employment. van Baardewijk:Bristol-Myers Squibb: Employment. Steegmann:Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau.

Abstract 2481 Poster Board II-458 Objective: With the pressure on healthcare budgets, it has become increasingly important for healthcare decision makers to consider the value for money of the treatments they reimburse. The objective of this analysis was to evaluate the long term outcomes and costs of rituximab in combination with cyclophosphamide/vincristine/prednisolone chemotherapy regimen (R-CVP) versus CVP alone, in previously untreated patients with indolent Non-Hodgkin Lymphoma (NHL) from the Portuguese National Health System (NHS) perspective. Methods: Cost-effectiveness (Life Years Gained - LYG) and cost-utility analysis (Quality Adjusted Life years – QALYs) were performed for a time horizon of 10 years, according to a Markov economic model with three health states (“progression free survival”, “progression” and “death”) and monthly cycles for a population of previously untreated patients with indolent NHL. Data from a phase III clinical trial (Marcus 2007) was used and expanded to include unpublished 53-month median follow-up data. Survival after first-line therapy was estimated from the Scotland and Newcastle Lymphoma Group registry data and utilities were derived from a study in the UK performed in patients with follicular lymphoma. Resource consumption was estimated by a Portuguese expert panel (Delbecq Panel). Costs were calculated from the Portuguese NHS perspective through official data with prices updated to 2008. Only direct medical costs were considered. Costs and clinical outcomes were discounted at 5% per annum. Deterministic and probabilistic sensitivity analysis were performed around assumptions on the time horizon, costs, utilities and excess mortality rate due to progression applied in the base-case analysis. Results: The 10-year base-case analysis showed a lower total cost per patient with CVP alone (€ 85,838) in comparison with R-CVP (€ 87,774). Life expectancy and quality-adjusted life expectancy per patient were higher with R-CVP (6.361 and 4.166, respectively) than with CVP alone (5.557 and 3.438, respectively), representing increases of 0.804 in LYG and 0.728 (8.7 months) in QALYs gained. The incremental cost per LYG was € 2,407 and the incremental cost per QALY gained was € 2,661. The probabilistic sensitivity analysis confirmed the robustness of the base-case analysis results. Conclusions: This study demonstrates that the combination R-CVP in previously untreated non-Hodgkin lymphoma patients improves life expectancy and is a cost-effective alternative to CVP in Portugal. Disclosures: Braga: Roche Farmacêutica Química, Lda: Employment. Pereira:Roche Farmacêutica Química, Lda.: Employment.

Acute lymphoblastic leukemia (ALL) is much rarer in adult age than in childhood, accounting for less than a quarter of acute leukemias, and with an overall survival rate at 5 years below 38%. The authors report the group experience in the treatment of adult ALL with HyperC-VAD protocol. From 2004 to 2007, 21 patients with adult ALL (15 male/6 female), with a median age at diagnosis of 29 years [18;58], were treated: four with ALL-L3/Burkitt lymphoma, six with T cell ALL/lymphoblastic lymphoma, eight with B cell ALL/lymphoblastic lymphoma, and three with ALL with t(9;22). The protocol consists of 4 courses of HyperC-VAD (cyclophosphamide 300mg/m2 IV q12h, on days 1–3; vincristine 2mg IV qd, on days 4 and 11; doxorubicin 50mg/m2 IV, on day 4; dexamethasone 40mg IV/PO qd, on days 1–4 and 11–14) that alternate with 4 courses of HD MTX-ARAC (methotrexate 1g/m2 IV, on day 1; cytarabine 3g/m2 IV q12h, on days 2–3). Those patients with ALL with t(9;22) received imatinib 400mg IV qd, on days 1–14 of each course; and CD20-positive cases received rituximab 375mg/m2 IV qd, on days 1 and 11 (odd courses) or on days 1 and 8 (even courses) of the first 4 courses. All patients received central nervous system prophylaxis in each course with methotrexate 12mg intrathecal on day 2 and cytarabine 100mg intrathecal on day 8. All patients (21/21) achieved complete remission after the first course of chemotherapy. Two patients abandoned the protocol due to neurologic and hematologic toxicity. The relapse rate was 47.6% (10/21), and the overall survival was 61.9% (13/21) – all deaths were due to disease progression. Overall, 131 courses were completed (69 odd courses/62 even courses). The most frequent complication was febrile neutropenia (32.8% - 18 in odd courses; 25 in even courses). The most severe complications were gram-negative septic shock (2 in even courses) and severe axonal polyneuropathy (1 in an odd course; 1 in an even course). Although these results are consistent with the literature, a longer follow up is needed to draw definitive conclusions.