ALBERT

Description: INTRODUCTION:Acute promyelocytic leukemia (APL) is the most curable acute leukemia in adults. Advancements in therapeutics such as the use of tretinoin (ATRA) and arsenic trioxide (ATO) have led to an overall survival of over 90% in 5 years. Early mortality, however, remains a major component of overall mortality in this disease and prompt recognition and initiation of adequate treatment has always been considered the most effective strategy to prevent it. Recent reports, though, have failed to show the benefit of prompt ATRA ministration in early mortality, once APL is suspected. These reports come mainly from high-income countries with swift and widespread access to health care services that are capable of recognizing, diagnosing and treating APL in a timely manner. We hypothesized, therefore, that in a lower income country, in a limited resources setting, prompt ATRA administration would improve early mortality in the setting of APL. METHODS: This is a retrospective, single-center study. We included all patients with APL diagnosis, confirmed by molecular or cytogenetics analysis treated in our institution, from January 1999 to May 2018. Until 2006, patients were treated with a modified AIDA regimen (ATRA plus mitoxantrone). After 2006, patients were treated with the International Consortium on Acute Promyelocytic Leukemia - ICAPL protocol (ATRA plus daunorubicin). This was a combined effort of the American Society of Hematology and of healthcare institutions from Latin American countries to improve outcomes in APL through improvements in therapeutics, education of healthcare professionals and expanded access to molecular diagnosis. We retrieved and reviewed patients' records for the time interval from disease presentation until the first hospital admission, and from hospital admission to the first dose of ATRA. We also looked for diagnostic variables that could be related with 30-day survival. RESULTS:Between January 1999 and May 2018, 83 APL patients were evaluated. Table 1 summarizes patients' characteristics. Medical records were available for 81/83 patients; 4 of them did not receive ATRA and died less than 7 days after their presentation. At diagnosis, median age was 37 years, 51.9% of patients were female, 26% were high-risk, 77.8% had bleeding symptoms, 72.8% had abnormal coagulation tests, and 12.3% had an elevated serum creatinine. Seventy-five percent were treated under the IC-APL protocol. Median time from disease presentation to the first hospital admission was 14.3 days (1-64 days) and median time to administration of ATRA after hospital admission was 18.2 hours (0.47-95.47 hours). Time to ATRA administration was significantly higher in patients who died in the first 30 days after diagnosis (median 27.46 vs.15.52 hours p=0.037) and who were treated with the modified AIDA (median 25.04 hours for the modified AIDA vs. 15.2 hours for the IC-APL protocol, p=0.037). Early administration of ATRA (less than 24 hours after the first hospital admission) was associated with a higher 30-day survival (89.4% vs. 63.3%, p=0.007; 75.3% for the whole cohort - Figures 1A and B). This benefit was seen mainly in patients with low or intermediate Sanz's risk score (Figures 1C and D). Serum creatinine, leukocytes count, and Sanz's risk were also predictive of 30-day survival in the whole cohort. There was no correlation between time from disease presentation to first hospital admission with 30-day survival. CONCLUSIONS: Our data support the role of early ATRA administration in the reduction of 30-day mortality in patients with recently diagnosed APL. This contrasts with previous findings from high-income countries that did not support such a benefit. We should highlight that in these cohorts the median time for ATRA administration was longer, which could explain the conflicting results. Furthermore, patients in high-income countries access health services early in their disease course, which could hamper any benefit from early ATRA administration. The correlation of early ATRA administration with the institution of IC-APL protocol underscores the importance of initiatives that promote the education of healthcare professionals and access to diagnostic tests of complex hematological diseases in low-income settings. Disclosures Pagnano: Abbvie: Consultancy; EMS: Other: Financial support for participation in congress; Novartis: Consultancy; Shire: Other: Lecture.

Description: INTRODUCTION: Autologous stem cell transplantation (ASCT) is the cornerstone of the treatment of several hematological malignancies, including multiple myeloma (MM) and aggressive and relapsed/refractory lymphomas. The mobilization of peripheral blood stem-cells (PBSC) for ASCT, however, is not always possible, with failure rates around 20%. Although the introduction of drugs such as plerixafor has greatly improved on this issue, they are still expensive and inaccessible in lower-income countries. The use of chemomobilization with drugs such as cyclophosphamide, etoposide, and others are a more affordable option, but they still lead to severe neutropenia, and in some settings to longer inpatient stays, with the associated costs. Vinorelbine is a vinca alkaloid which has already been reported to be effective in PBSC mobilization in combination with granulocyte growth-factor (G-CSF). We tested whether vinorelbine-based strategy for PBSC mobilization would be more effective and less resource-consuming than mobilization with conventional chemotherapy in combination with GCSF. METHODS: This is a retrospective, single-center analysis of the 74 patients with plasma cell disorders and lymphomas who underwent PBSC mobilization in our institution from January 2016 until May 2018. Until March 2017 PBSC mobilization at our institution was done with cyclophosphamide 2 gm/sqm plus G-CSF, for plasma-cell disorders, or with conventional chemotherapy regimens, such as ICE (ifosfamide, carboplatin and etoposide) and DHAP (dexamethasone, cytarabine and cisplatin) plus G-CSF for lymphomas. Peripheral CD34+ cells were counted daily after white blood cells reached 〉 1000 cells/μl, and leukapheresis was performed on the first day of peripheral CD34+ cell count 〉 10/μl, with a target of at least 2x106CD34+ cells/kg. Due to local limitations and the unpredictability of the day of PBSC harvesting, the whole procedure-from chemotherapy administration to apheresis-was done in the inpatient setting. From March 2017 onwards, in an effort to reduce costs and increase efficacy, a vinorelbine-based protocol for mobilization with a 35 gm/sqm dose on day one, GCSF 12-16 mcg/kg/day from day 4 onwards and PBSC harvesting on day 8, or latter, when peripheral CD34+ cell count was higher than 10/μl was implemented for all patients, irrespective of their diagnosis. RESULTS: Patients' characteristics are summarized in Table 1. Seventy-four patients underwent mobilization, 38 (51.3%) with vinorelbine and 36 (47.3%) with conventional chemotherapy, with an 81.1% success rate. Patients had a median age of 54 years, with a median of one previous treatment line, which included radiotherapy in 22.4% of patients. Plasma-cell disorders were the most frequent diagnosis (59.5%). Due to a shortage of melphalan, only 52.7% of patients have proceeded to ASCT so far. Vinorelbine-based PBSC mobilization resulted in higher success rates (92.1% vs. 69.4%, p=0.017), lower length of hospital stay (median of 3 vs. 16 days, p

Description: INTRODUCTION: JAK2V617F mutation is independently associated with a higher risk of venous thromboembolic events (VTE) in myeloproliferative neoplasms (MPN). We have previously shown that endothelial colony-forming cells (ECFCs) from JAK2V617F MPN patients do not express this mutation but exhibit a pro-adhesive phenotype with a lower in vitro angiogenic potential. Here, we explore the mechanisms through which ECFCs from JAK2V617F MPN patients behave differently from ECFCs from healthy individuals. METHODS: We selected 38 patients with newly or previously diagnosed MPN, regardless of current or prior hydroxyurea therapy, with or without a history of VTE. Plasma levels of ADAMTS13, P-selectin, soluble VCAM, soluble ICAM, PDGF-AA, PDGF-AB/BB, IL-8, IL-1β, and soluble CD40 ligand were measured through the use of a multiplex assay. We then tried to isolate ECFCs from 20 of the JAK2V617F patients as well as 14 healthy individuals. Successfully isolated ECFCs were then submitted to co-culture with red blood cells (RBC), after which RNA was extracted from ECFCs. ADAMTS13, P-selectin, sVCAM, and sICAM were measured in the supernatant from ECFCs and RBC co-culture with multiplex assay. ECFCs' surface expression of P-selectin, VCAM, ICAM, and E-selectin was measured with the use of flow cytometry. Gene expression in RNA from co-cultured ECFCs was assessed with two 84-gene RT-PCR arrays for endothelial cell biology and signal transduction pathways (RT2 Profiler PCR array, Qiagen®). RESULTS: Recruited patients had polycythemia vera (PV) (n=17), primary myelofibrosis (PMF) (n=7) and essential thrombocythemia (ET) (n=14); 34% of them had had a previous VTE (6/17 PV; 3/14 ET and 4/7 PMF). Median age was 59 years (26-88), 23% were male. Compared with JAK2wt, JAK2V617F MPN patients (n=29) showed higher median concentrations of sVCAM (1063 vs. 786.5 ng/ml, p=0.0315), sCD40L (339 vs. 166.4 ng/ml, p=0.0065), PDGF-AA (430.6 vs. 136.5 ng/ml, p=0.03) and PDGF-AB/BB (1068 vs. 365.8 ng/ml, p=0.004). Success in ECFC isolation was 9/20 (45%) in JAK2V617F MPN patients and 8/14 (57%) in healthy individuals. None of the ECFCs from JAK2V617F MPN patients expressed this mutation. In comparison with ECFCs from healthy individuals, ECFCs from JAK2V617F MPN patients did not show a higher expression of either VCAM1, ICAM, P-selectin, and E-selectin, as measured by flow cytometry after co-culture with RBCs. Multiplex assay on the supernatant of this co-culture did not show any difference in the levels of ADAMTS13, sVCAM, sICAM, and sP-selectin. RNA PCR array from the ECFCs after co-culture with RBCs showed no difference in the expression of adhesion molecules when compared with ECFCs from healthy individuals, except for the increased expression of ADAM17 (fold regulation: 5.46, p=0.006), a metalloprotease involved in the shedding of adhesion molecules, among them VCAM1. ECFCs from MPN patients did not show higher activation of the JAK-STAT pathway but had a lower expression of WNT5 (fold regulation: -2.22, p=0.03), indicating a reduced activation of the Hedgehog pathway, suitable with the reduced in vitro angiogenesis capacity of these cells. CONCLUSIONS: JAK2V617F MPNs are associated with an increase in circulating adhesion molecules, such as sVCAM, and platelet activation markers. The pro-adhesive phenotype and lower angiogenic potential of ECFCs JAK2V617F MPN patients are not related to this mutation, which is not expressed in these cells and might be related to an increased expression of ADAM17 and reduced activation of the Hedgehog pathway. Disclosures Ozelo: BioMarin: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Novo Nordisk: Research Funding; Roche: Research Funding.