Management of Venous Thromboembolism (VTE) in Patients with Acute Leukemia: Results from a Multicenter Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3688-3688 ◽  
Author(s):  
Mariasanta Napolitano ◽  
Luca Valore ◽  
Giorgia Saccullo ◽  
Alessandra Malato ◽  
Calogero Vetro ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Acute Leukemia ◽  
Conflicts Of Interest ◽  
Sinus Thrombosis ◽  
Lymphoblastic Leukemia ◽  
Laboratory Data ◽  
Induction Phase ◽  
Severe Thrombocytopenia ◽  
Significant Difference ◽  
Clinical Records

Abstract Background In the last decades, evaluation of thrombotic complications secondary to acute leukemia (AL) has been poorly investigated. Only scant data are available on management and prevention of thrombosis in this setting. We performed a multicenter retrospective study with the aim to evaluate the management of venous thromboembolism (VTE) in patients with AL and to report the most commonly adopted regimens of treatment. Materials and methods Available clinical records of out and in-patients diagnosed with AL from January 2008 to June 2013 in 7 Reference Regional Hospitals were analyzed. Cases of VTE, including thrombosis in atypical sites [Retinal occlusion (RO) and Cerebral Sinus Thrombosis (SCT)], were reported. All data were recorded in a dedicated electronic database. The patient’s basic demographic data (age, gender, race), medical history, disease-related information, and laboratory data were extracted. Instrumental diagnosis of deep vein thrombosis (DVT), pulmonary embolism (PE) and RO and SCT was performed according to ACCP guidelines. Data were collected and analysed by the IBM SPSS Software 21.0 version (SPSS, Inc., Chicago, Ill, US) and the Epi Info software, version 3.2.2, (Centers for Disease Control and Prevention). Statistical analysis of quantitative and qualitative data, included descriptive statistics, was performed for all the items. Results Over a population of 1461 patients with AL, 99 (6.8%) cases of VTE were recorded, mainly in hospitalized patients: 72 cases were associated with Acute Myeloid Leukemia (AML) and 27 with Acute Lymphoblastic Leukemia (ALL), with a mean age of 52.2 ± 15.4 years (median age: 53years). In particular the incidence/ratio over the sub-population of AML-patients was 6.0%, that is 72/1191 cases; with a mean age of 54.7 ± 14.3 years (median age: 57 years). VTE occurred during chemotherapy (CHT) in 90/99 (90%) cases, mainly during the induction phase of treatment (in 70% of cases ),the remaining 9 cases were diagnosed in concomitance with acute leukemia. In both subgroups with VT, there was no statistical significant difference between time at diagnosis of VT and time at diagnosis of AL. Treatment of VTE was mainly based on Low Molecular Weight Heparin (LMWH), in accordance with results from previous studies and current guidelines (full dosage for the first month from diagnosis and reduced dosage at 75% for the following months). Thrombocytopenia occurred in 55 patients at diagnosis of AL, in 33 cases platelets were <50x109/L. Most VTE episodes (73/99, 73.7%) were treated with LMWH as above reported . In patients with moderate/severe thrombocytopenia, a dose adjusted to platelet count was adopted; most of the investigators used LMWH at prophylactic dosage. Two cases received fondaparinux, one patient was treated with unfractioned heparin; six cases did not receive any treatment due to severe thrombocytopenia. No cases of VT–related deaths nor fatal complications during treatment for VTE were reported. All treatments with LMWH lasted from 3 to 6 months. All patients clinically recovered from VTE, only 2 late recurrences (PEs) were observed. Conclusion VTE can complicate the clinical course of AL in a not negligible percentage of cases. Anticoagulant treatment schedules and duration in patients with AL are influenced by many factors, mainly related to chemotherapy and severe thrombocytopenia. In the analyzed subset of patients, full dose treatment with LMWH for at least one month followed by a dose reduction for at least three months was appropriate. Disclosures No relevant conflicts of interest to declare.

scholarly journals Incidence and Management Of Venous Thrombosis In Acute Leukemia: A Multicenter Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3890-3890
Author(s):  
Mariasanta Napolitano ◽  
Luca Valore ◽  
Giorgia Saccullo ◽  
Alessandra Malato ◽  
Calogero Vetro ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Venous Thrombosis ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Categorical Variables ◽  
Severe Thrombocytopenia ◽  
Mediastinal Disease ◽  
Significant Difference ◽  
Coagulation Tests ◽  
Clinical Records

Abstract Background Venous thrombosis (VT) frequently complicates the clinical course of cancer. Reported incidence of VT in many hematological neoplasms is up to 10%, a value comparable to that of solid tumors. Available data on the incidence and management of VT in Acute Leukemia (AL) are scanty and quite discordant. We have performed a multicenter retrospective study with the primary objective to evaluate the incidence of venous thrombotic complications in a population of patients with AL. Secondary objective was to evaluate the management of these complications in patients with AL. Materials and Methods Available clinical records of out and in-patients diagnosed with AL from January 2008 to June 2013 in 4 Regional Reference Hospitals were analyzed. Cases of venous thrombosis (VT), including thrombosis in atypical sites [Retinal occlusion (RO) and Cerebral Sinus Thrombosis (CST)], were reported in the current study. All data were recorded in a dedicated database. Available laboratory tests at diagnosis of VT included complete blood cells count (CBC), basal coagulation tests (PT, aPTT, fibrinogen), Antithrombin, anticoagulant Protein S and C and D-dimer. Instrumental Diagnosis of deep vein thrombosis (DVT), pulmonary embolism (PE) and RO and CST was performed according to ACCP guidelines. In the statistical analysis, logistic regression model was applied. Fisher’s exact test was used to determine relationships between categorical variables. All P-values represented were two-sided, and statistical significance was declared when P< 0.05. Results Over a population of 831 patients with AL, 37 cases of VT were recorded, mainly (34/37 cases) in hospitalized patients: 24 cases were associated with Acute Myeloid Leukemia (AML) and 13 with Acute Lymphoblastic Leukemia (ALL). In the cohort of patients with VT, 23 were males (14 with AML, 9 with ALL) and 14 females (4 with AML, 10 with ALL), with a mean age of 46 ± 13,1 years; mean age of patients with AML and VT was 49 ± 12,8 years; mean age of patients with ALL and VT was 40,2 ± 12,2 years. Twelve patients presented at least a concomitant chronic disease; no one was receiving anticoagulant prophylactic treatment with low molecular weight heparin (LMWH) during hospitalization. There were 23 cases of DVT of upper arms, 9 cases of proximal DVT of limbs (one complicated with PE), 2 cases of RO, 1 of CST and 1 case of intracardiac clot. In 28/37 (75,6%) cases of recorded VT, a central venous catheter (CVC) was placed (Figure 1); moreover, 21/23 events of DVT of upper arms were significantly associated with a CVC insertion (p< 0.01). In the other 2 cases, one patient had a bulky mediastinal disease and 1 was diagnosed with promyelocytic AML. VT occurred during chemotherapy (CHT) in 32/37 (86.4%) cases, the remaining 5 cases were diagnosed in concomitance with leukemia: in 20 cases, VT occurred at induction, in 7 at consolidation and in 5 during salvage CHT. In both subgroups with VT, there was no statistical significant difference between time at diagnosis of VT and time at diagnosis of AL. At CBC, thrombocytopenia was the most frequently observed laboratory abnormality. Basal coagulation tests and anticoagulant levels were normal in all cases. Inherited prothrombotic mutations were available only for 9/37 cases, 1 case was heterozygous for Factor V Leiden and 1 for Factor II (G20210A) mutation. Most VT episodes (32/37) were treated with LMWH at therapeutic doses for the first month after diagnosis, a dose reduction was recorded in the following months, mainly related to severe thrombocytopenia after CHT ; 1 case was treated with unfractioned heparin; four cases did not receive any treatment due to severe thrombocytopenia. No cases of VT–related deaths nor fatal complications during treatment for VT were recorded. Treatments with LMWH lasted from 3 to 6 months. All patients clinically recovered from VT, only 2 late recurrences (PEs) were observed. Conclusions The incidence (4.5%) of VT in the analyzed cohort of patients with AL is almost similar to only one previous report, even if the involved sites distribution appears quite different. In particular, RO has never been reported. Atypical sites VT must be suspected to be correctly diagnosed and treated. Anticoagulant treatment schedules and duration in patients with AL is influenced by many factors, mainly related to CHT and severe thrombocytopenia. The optimal management of VT in patients with AL requires further, prospective studies. Disclosures: No relevant conflicts of interest to declare.

Prognostic Impact of a Novel Biomarker, Serum Soluble LR11 on Acute Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2717-2717
Author(s):  
Chikako Ohwada ◽  
Masahiro Takeuchi ◽  
Shio Sakai ◽  
Daijiro Abe ◽  
Yusuke Takeda ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Hematological Malignancies ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Laboratory Data ◽  
Type I ◽  
Prognostic Impact ◽  
Soluble Lr11

Abstract Abstract 2717 Introduction: LR11 (also called SorLA or SORL1) is a type I membrane protein, from which a large extracellular part, soluble LR11 (sLR11), is released by proteolytic shedding. LR11 plays a key role in the migration of undifferentiated vascular smooth muscle cells, and circulating sLR11 is known to be a biomarker of carotid intima-media thickness. Along with the fact that circulating sLR11 levels represent the accumulation of vascular immature cells, human CD34+CD38− immature hematopoietic precursors have been reported to express high levels of LR11 mRNA. We have recently found that LR11 is specifically and highly expressed on cell surface of acute leukemia cells in addition to normal leukocytes (unpublished data). These facts prompted us to evaluate the serum sLR11 level in patients with acute leukemia and other hematological malignancies to validate sLR11 as a novel circulating marker for treatment outcome and prognosis. Patients and Methods: Serum sLR11 levels were measured by ELISA method in 139 patients with acute leukemia and other hematological malignancies treated at a single institution from 1999 to 2010. Patients' laboratory data and treatment outcome were collected retrospectively in 43 acute myeloid leukemia (AML) and 23 acute lymphoblastic leukemia (ALL) patients. Results: sLR11 levels of acute leukemia patients were significantly increased [ALL, 73.5±93.5 ng mld−1 (range, 5.7–407.0), P<0.0001; AML, 26.8±29.1 ng ml−1 (range, 5.0–157.5), P<0.0001] in comparison to the control subjects (9.2±3.3 ng ml−1), while sLR11 levels in patients with chronic myeloid leukemia (17.9±11.1 ng ml−1), chronic lymphocytic leukemia (12.7±11.6 ng ml−1), multiple myeloma (10.5±4.8 ng ml−1), and POEMS syndrome (9.0±2.7 ng ml−1) were not significantly different from controls. sLR11 levels were significantly higher in ALL than those in other leukemias. Paired sample analysis of patients with AML and ALL at complete remission (CR) after chemotherapy showed significantly decreased sLR11 levels compared to the time of diagnosis (AML: 30.9±37.5 ng ml−1 vs. 10.4±4.3 ng ml−1, P=0.015, ALL: 39.1±126.0 ng ml−1 vs. 11.2±5.0 ng ml−1, P=0.0029). The multiple stepwise liner regression analysis showed that the peripheral blast proportion in both ALL and AML patients were independently associated with sLR11 at diagnosis (AML: r2= 0.21, P=0.0026, ALL: r2= 0.34, P=0.0043). Among 42 AML patients, sLR11 levels of subjects in the highest tertile of peripheral blast proportion (>67.5% of WBC) were 2.44- and 3.05-fold higher than those in the middle (23.0-64.0% of WBC) and lowest tertiles (<20.0% of WBC), respectively. Twenty out of 21 AML patients with <20 ng ml−1 sLR11 at diagnosis achieved CR after induction chemotherapy, and the CR rate was significantly higher in patients with <20 ng ml−1 sLR11 than in patients with ≥20 ng ml−1 (95.2% vs 65.5%, P=0.02). The probability of overall 5-year survival was significantly lower in AML patients with ≥20 ng ml−1 sLR11 at diagnosis than in those with <20 ng ml−1 [Figure1, 36.8% vs 63.7%, P = 0.04; hazard ratio (HR): 2.74; 95% confidence interval (CI): 1.04–8.01]. Conclusions: Serum sLR11 levels in patients with acute leukemia were significantly elevated and were associated with the peripheral blast population but not in other chronic proliferative hematological malignancies. These findings suggest that the serum sLR11 levels are predictive for pathogenic properties of immature blasts, including their migration and attachment activities, rather than simply associating with proliferating cell numbers. Especially in AML patients, serum sLR11 levels at diagnosis significantly affect CR rate and OS. Although larger scale studies including karyotype or FAB classification would be required for its patho-clinical significance, serum sLR11 is a promising novel biomarker for acute leukemia and it could play an important role as prognostic factor. Disclosures: No relevant conflicts of interest to declare.

Pediatric Therapy In Adult Acute Lymphoblastic Leukemia: Updated Experience of a Single Centre

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4338-4338
Author(s):  
Stefania Paolini ◽  
Sarah Parisi ◽  
Ilaria Iacobucci ◽  
Cristina Papayannidis ◽  
Maria Chiara Abbenante ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Hematological Toxicity ◽  
Induction Phase ◽  
Single Centre ◽  
Phase Ib ◽  
Small Series ◽  
Significant Difference

Abstract Abstract 4338 Background. Acute lymphoblastic leukemia (ALL) presents with different outcome in children and adults, with event-free-survival (EFS) rates of 70–80% and 30–40% at 5 years, respectively. This reflects both a different disease biology and different therapeutic approaches. Recently, results apparently improved in young adults/adolescents aged 15–21 years, with de novo ALL, when treated with pediatric intensive regimens rather than with typical adult regimens. Similarly, clinical studies are ongoing in older patients, toxicity related-therapy seeming the limiting issue. Aims. We report a single centre experience on adult ALL patients treated with an intensive pediatric-inspired schedule, designed to assess its tolerability and efficacy. Methods. From November 2007 to June 2010 seventeen ALL patients (M/F=12/5) were treated at our Center according to a modified AIEOP LAL2000 regimen. Treatment consisted of 7 days steroid pre-treatment, and four drugs 78-days induction (phase IA and phase IB) after which high risk (HR) patients were treated with three polychemotherapy blocks, while intermediate (IR) and standard risk (SR) patients went on 8-weeks consolidation and subsequent delayed intensification. Allo-SCT was planned for all patients with HLA-matched donor, as alternative to 2-years maintenance therapy. Median age was 31 years (range, 17–47). According to cytogenetic, response to steroid and minimal residual disease patients were classified into HR (n=7), IR (n=6) and SR (n=4). Results. 15/17 patients completed the induction phase IA, two being out for toxicity (grade IV infection and intestinal occlusion). Twelve (71%) obtained a complete remission (CR); three were refractory. However, one of them subsequently achieved CR after polychemotherapy blocks, for an overall response rate of 76% (13/17). Eleven patients then completed the 28-days induction IB. One patient is ongoing. Median induction duration was 92 days (range 82–136). Delays were mostly due to extra-hematological toxicity, the commonest being gastrointestinal (n=12), infective (n=7) and thrombotic (n=3). Delays were accumulated in both induction phases without significant difference between phase IA (median 18.5 days, range 4–37) and phase IB (median 17 days, range 9–66), despite an absolute number of moderate-severe AE superior in phase-IA versus phase-IB (12 vs 5). After induction, 4/12 patients already received consolidation therapy; 2/4 then received allo-SCT. The median duration of consolidation was 51 days (range 22–94). Conversely, 6/12 patients received polychemotherapy-blocks, one patient went directly on alloSCT and the remaining is ongoing. After polychemotherapy-blocks, five out six patients received allo-SCT. The median CR duration was 13 months (range 1+-42+); two patients relapsed, both after allo-SCT. With a median follow-up of 11 months (range 2–43) 11/17 (65%) patients are alive, 9 in CR (5 undergone allo-SCT). Six patients dead, three in CR for infectious complications, 3 for relapsed/refractory disease. Conclusions. Though in a small series, pediatric-like intensive chemotherapy seemed to be feasible in adult ALL. Extra-hematological toxicity, however, caused significant treatment delays during induction. Finally, the overall outcome appeared promising, though longer follow-up and larger populations are needed to draw definitive conclusions. Acknowledgments. BolognAIL, European LeukemiaNet, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, PRIN 2008, Ateneo RFO, Project of Integrated Program (PIO), Programma di Ricerca Regione – Università 2007–2009. Disclosures: No relevant conflicts of interest to declare.

Philadelphia-Like Signature In Childhood Acute Lymphoblastic Leukemia: The AIEOP Experience

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 353-353 ◽  
Author(s):  
Geertruy te Kronnie ◽  
Daniela Silvestri ◽  
Elena Vendramini ◽  
Grazia Fazio ◽  
Franco Locatelli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Gene Expression Signature ◽  
Induction Phase ◽  
Dna Index ◽  
Study Gene Expression ◽  
Significant Difference

Abstract Background Despite the current risk-based stratification and therapies, up to 20% of pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) experience relapse. A major research effort is dedicated to identifying poor prognostic subgroups in the larger subset of patients with intermediate-risk disease, where most relapses occur. Recently, two groups in the US and the Netherlands independently identified a novel BCP-ALL subtype negative for the BCR/ABL fusion gene but with a gene-expression profile similar to Philadelphia chromosome-positive (Ph+) ALL. This ‘Ph-like’ (or ‘BCR/ABL-like') subtype encompasses 10-15% of BCP-ALL patients, predicts high incidence of relapses and defines a candidate subgroup for targeted treatment with tyrosine kinase inhibitors and alternative drugs. Aim Aim of this project was to identify BCP-ALL Ph-like cases and their prognosis in patients treated in Study Protocols of the Italian Association of Pediatric Hematology and Oncology (AIEOP) Methods In the context of the Microarray Innovations in LEukemia (MILE) study, gene expression profiling was successfully performed on 400 Italian childhood BCP-ALL cases enrolled in AIEOP-BFM ALL2000/R2006 protocols, from whom material was available. The MILE classifier recognized the most common genetic subgroups, namely t(4;11), t(12;21), t(1;19) or t(9;22) positive, or high hyperdiploid (DNA index≥1.16). Out of 400 BCP-ALL cases, 143 negative for common fusion transcripts, non-high hyperdiploid (DNA index<1.16) and non-Down Syndrome, were defined as ‘B-others’. Results Using signatures of known ALL subgroups, the likelihood to be close to one of the ‘known’ classes was defined for each of the B-others samples. Specifically, 43 B-other cases (43/143=30.1%, about 10% of total BCP-ALL cohort) presented as a cluster with a gene expression signature close to the BCR/ABL signature, therefore referred to as ‘Ph-like’. Among B-others, Ph-like cases had a significantly increased proportion of males, age>10 years and WBC>20x109/L. The 5y event-free survival (EFS) of Ph-like patients was 54.8% (SE 8.2) vs 83.1% (3.9) in the remaining B-others patients (p<0.001), mostly due to an increased cumulative incidence of relapse (CIR: 33.9% (7.4) vs 14.9% (3.7); p=0.009). Notably, Ph-like patients did not differ for prednisone (PDN) and minimal residual disease (MRD) response or final risk stratification. Indeed, out of 36/43 stratified by MRD, only 7 patients had high-risk MRD, while 20 were MRD intermediate and 9 even MRD standard risk. Only 3 non-HR cases by MRD were then classified as HR based on PDN response. Of relevance, the significant difference in 5y EFS was confirmed in the 33 Ph-like patients with no HR features (59.8% (9.2) vs 88.5% (3.9) in the remaining B-others patients with similar features (p<0.001), with a significantly increased CIR (32.1% (8.4) vs 10.2% (3.7); p=0.005). Among 43 Ph-like cases, 1 was resistant and 1 died during the induction phase. Out of the 14 relapses, 10 were isolated medullary, and 4 combined with an extramedullary site (no CNS relapses). Two patients died in remission and no secondary malignancies occurred during the observation period. Overall, 25/43 (58.1%) Ph-like patients are alive in complete remission versus 84/100 (84.0%) in B-others, non Ph-like patients. Conclusions and perspectives We identified a ‘Ph-like’ subgroup in the Italian cohort of children with BCP-ALL, associated to a poor outcome. Ph-like patients, independently of the other known risk features, could be considered eligible for alternative treatments. The genetic characterization of this subgroup is ongoing within the AIEOP-BFM research trial cooperative group, which is aimed at further defining the pathogenetic mechanisms and identifying the therapeutic translation. Disclosures: No relevant conflicts of interest to declare.

Thromboembolic and Hemorrhagic Complications In Adult Patients With Acute Lymphoblastic Leukemia (ALL) Treated With Asparaginase-Containing Combination Chemotherapy: A Single Center Experience

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3873-3873 ◽  
Author(s):  
Jason N. Barreto ◽  
Kristen B. Mccullough ◽  
Candy S. Peskey ◽  
Michelle Elliott ◽  
Dennis A. Gastineau ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Sinus Thrombosis ◽  
Single Case ◽  
Lymphoblastic Leukemia ◽  
Activity Level ◽  
Adult Patients ◽  
Clinical Event ◽  
Induction Phase ◽  
Single Center ◽  
Treatment Protocols

Abstract Background L-asparaginase (LASP) depletion of asparagine reduces antithrombin (AT) and fibrinogen and is associated with thromboembolic (TE) and hemorrhagic events (HE). AT replacement in pediatric ALL patients demonstrated safety and potential benefit as thromboprophylaxis in a prospective, randomized trial.(Mitchell et al, 2003) Current consensus supports AT replacement when AT activity is below 60%.(Stock et al, 2011) The incidence of TE and HE in adults receiving AT repletion during LASP or pegylated asparaginase (PEGASP) requires further investigation. Methods This single center, retrospective, observational study was approved by the Mayo Clinic Institutional Review Board. Consecutive adult patients with a confirmed diagnosis of ALL receiving LASP or PEGASP containing chemotherapy regimens between January 2000 and October 2012 were evaluated. Patients with documented thrombophilia and pre-existing TE or HE were excluded. Patients receiving AT concentrate (ATC) compared to those that did not and were evaluated up to 60 days after the last LASP or PEGASP dose for objectively confirmed TE and HE. Results Of the 74 patients screened, 54 (73%) met inclusion criteria. Forty-seven (87%) received ATC and were evaluable. The remaining 7 (13%) did not meet follow up duration and were excluded from further analysis. Twenty-three (49%) patients received LASP, 20 (42%) received PEGASP and 4 (9%) received both. Distribution per treatment protocols was; CALGB 9111 (n=16 (34%), Larson et al, 1998), E2993 (n=12 (25%), Goldstone et al, 2008), C10403 (n=8 (17%), NLM: NCT00558519), CCG 1941 (n=6 (13%), Gaynon et al, 2006) and Augmented HyperCVAD (n=5 (11%), Faderl et al, 2011). A total of 1465 AT activity levels were analyzed, resulting in 378 doses of ATC. Ten patients (21%) experienced a clinical event, with all events occurring during cycle 1 of chemotherapy (table 1). Median time from last LASP or PEGASP dose to TE was 13 days (range 3-56) with a median of 4 days (range 3-13) from last ATC dose to TE. Median AT activity level at time of TE was 56% (range 47-72). Thrombotic events included; line-related deep vein thrombosis (LRDVT, n=7), cerebral venous sinus thrombosis (CVST, n=1) and pulmonary embolism (PE, n=1). One patient with cerebral hemorrhage constituted the only HE. All LRDVT occurred in central venous catheters and management included; line removal (n=3), anticoagulation (n=1), line removal and anticoagulation (n=2) and no intervention (n=1). The single case of PE was managed with anticoagulation. Two patients had a recurrent LRDVT in different locations during subsequent chemotherapy in spite of ongoing ATC supplementation. Conclusions The incidence of TE in adult ALL patients receiving LASP or PEGASP during induction chemotherapy with AT thromboprophylaxis was 19%. LRDVT was the most common TE with a comparable incidence to adult ALL patients not receiving ATC (15%) (Grace et al 2011). There was a small incidence of non-LRDVT (4%) and HE (2%). As induction-phase chemotherapy and placement of central lines are independent risk factors for thrombosis, the cost-effectiveness of AT replacement for prevention of TE during adult ALL treatment requires prospective evaluation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Hemorrhagic Cerebral Vascular Accident with Breakdown of Salt-Wasting Cerebral Syndrome in Acute Lymphoblastic Leukemia: Case Report

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 27-27
Author(s):  
Hugo Henrique de Freitas Ferreira ◽  
Alessandra Suelen Jardim Silva ◽  
Lenilton Silva DA Silva Júnior ◽  
Gustavo Henrique de Medeiros Oliveira ◽  
Maria das Graças Pereira Araujo ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Sinus Thrombosis ◽  
Lymphoblastic Leukemia ◽  
Laboratory Data ◽  
Specific Treatment ◽  
Laboratory Diagnosis ◽  
Sodium Concentration ◽  
Hemodynamic Instability ◽  
Lymphoid Leukemia ◽  
Salt Wasting

Introduction:Cerebral Salt Losing Syndrome (SCLS) is defined as a renal loss of sodium during intracranial disease, leading to hyponatremia and decreased volume of extravascular fluid. Studies show the existence of an association with hemorrhagic stroke (HCV) and SCLS as a complication that significantly contributes to the morbidity and mortality of patients with acute lymphoid leukemia (ALL).Objective:To report a case of a patient with ALL who presented HCV with neurological lesion, showing repercussions in the nervous system through SCPS.Case Description:A 33-year-old female patient was referred to the specialized hematology service, complaining of petechiae spread in the trunk and limbs, high fever, progressive asthenia, generalized pain in addition to nausea and vomiting. Laboratory data showed pancytopenia and IgM and IgG serology reagent for dengue. Cytomorphological examination of peripheral blood showed the presence of 68% of lymphoid blast cells, later confirming by bone marrow aspirate immunophenotyping as a CD10 negative pre-B ALL (pro-B ALL). After the start of chemotherapy treatment, the patient presented episodes of generalized tonic-clonic seizure crisis that were repeated in the two days that followed, in addition to referring to intense paresthesia in the upper limbs and headache and referred to the Intensive Care Unit (ICU). Imaging exams showed heterogeneous right frontal hemorrhage compatible with HCV, and sagittal sinus thrombosis, with an increase in frontal hematoma with deviation of centro medial structures. Subsequently, he presented high urinary output (6,500 mL / 24 hours) with severe polydipsia, in addition to hyponatremia (129), hypouricemia (20) and decreased creatinine (0.3), urinary sodium concentration and urinary osmolarity, evolving with dehydration (+++ / 4+) and hemodynamic instability, establishing the diagnosis of SCPS. After intervention with flourcortisone and hydroelectrolytic replacement, the patient presented an improvement in the condition of SCLS and, with significant clinical improvement, the patient continues on specific cancer treatment, and without neurological sequelae.Conclusion:The correct clinical and laboratory diagnosis allows an early and safe intervention. Knowledge of this clinical entity enables specific treatment and a favorable outcome for the patient. Disclosures No relevant conflicts of interest to declare.

scholarly journals A Novel Engineered Single-Chain Antibody Fragment for Targeting Pediatric Philadelphia Chromosome-like Acute Lymphoblastic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-36
Author(s):  
Sara M.A. Mohamed ◽  
Keith Sia ◽  
Karl-Heinz Friedrich ◽  
Andreas Wohlmann ◽  
Savvas Savvides ◽  
...  
Keyword(s):  
Indirect Immunofluorescence ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Statistical Significance ◽  
Immunofluorescence Assay ◽  
Laser Scanning Microscopy ◽  
Indirect Immunofluorescence Assay ◽  
Single Chain ◽  
Genetic Characteristics ◽  
Significant Difference

Introduction: Philadelphia-like acute lymphoblastic leukaemia (Ph-like ALL) is a high-risk ALL subtype characterized by an inferior survival rate and chemotherapeutic drug resistance (Tasian et al, Blood 130: 2064-2072, 2017). Around 50% of Ph-like ALL cases harbour gene rearrangements leading to the overexpression of cytokine receptor-like factor 2 (CRLF2) (Loh et al, Blood 121: 485-488, 2013). CRLF2 (also known as thymic stromal lymphopoietin receptor, TSLPR) heterodimerizes with the interleukin-7 receptor alpha (IL-7Rα) subunit to form the functional TSLPR. Upon TSLP binding, CRLF2 activates the JAK/STAT signalling pathway, leading to enhanced proliferation and survival of leukemia cells resulting in poor outcomes in patients (Harvey et al, Blood 115: 5312-5321, 2010). The extracellular overexpression of CRLF2 and association with poor prognosis suggest the translational value of designing precision-based therapeutics targeting CRLF2 in Ph-like ALL. Although conventional immunotherapy using full-sized antibodies is a promising treatment strategy that can improve treatment efficiency and minimize off-target toxicity, their clinical translation is challenging due to the high production cost and large size affecting targeting efficiency (Holliger et al, Nat Biotech 23: 1126-1136, 2005). Herein, we validated a novel single-chain variable fragment against CRLF2 (CRLF2-ScFv) for targeting Ph-like ALL cells. Methods: A CRLF2-rearranged Ph-like ALL cell line (MHH-CALL-4) was lentivirally transduced with a CRLF2-targeting shRNA driven by an inducible promoter, enabling the inducible knockdown of CRLF2. CRLF2 expression in MHH-CALL-4 cells after shRNA induction (KD-CALL-4) was evaluated using fluorescence-activated cell sorting (FACS). The cellular association of the CRLF2-ScFv was determined in MHH-CALL-4 and KD-CALL-4 at 4° and 37°C using an indirect immunofluorescence assay. Confocal laser scanning microscopy was used to visualize and compare the cellular association of CRLF2-ScFv in MHH-CALL-4 and KD-CALL-4. The cellular association of CRLF2-ScFv was also investigated ex vivo using a small panel of Ph-like and non-Ph-like ALL patient-derived xenografts (PDXs), representing similar immunophenotype and genetic characteristics to their original disease subtypes (Liem et al, Blood 103: 3905-3914, 2004), and peripheral blood mononuclear cells (PBMCs) to investigate the non-selective association. CRLF2 expression in MHH-CALL-4 and Ph-like ALL PDX cells was quantified using indirect immunofluorescence assay. The downstream impact of CRLF2-ScFv on STAT5 phosphorylation (pSTAT5) was determined by FACS either with or without TSLP stimulation. The statistical significance was tested using Unpaired unequal variances t-test or one-way ANOVA followed by multiple comparisons test. Statistical significance was considered when P ≤ 0.05. All experiments were performed in triplicate. Results: KD-CALL-4 showed a 75% reduction in CRLF2 expression compared with MHH-CALL-4 cells (P = 0.0009). CRLF2-ScFv exhibited a 94% higher association with MHH-CALL-4 compared with KD-CALL-4 cells at 37°C (P = 0.0013). The association of CRLF2-ScFv with MHH-CALL-4 cells was reduced by 75% at the non-proliferating state of cells at 4°C compared to 37°C (P = 0.006). Orthogonally viewed confocal microscopy images showed 82% higher intracellular uptake of CRLF2-ScFv in MHH-CALL-4 compared to KD-CALL-4 cells (P = 0.0003). CRLF2-ScFv showed &gt;80% higher association with a Ph-like PDX sample compared with a control CRLF2low PDX and PBMCs (P &lt; 0.001). Of note, a Ph-like ALL PDX exhibited only one-third of the association with CRLF2-ScFv compared with MHH-CALL-4 cells (P = 0.04), corresponding to the significant difference in CRLF2 surface expression (P = 0.01). CRLF2-ScFv significantly reduced pSTAT5 expression in MHH-CALL-4 cells (P = 0.05) and prevented TSLP-induced STAT5 phosphorylation (P = 0.01), suggesting competition with the TSLP binding site. Conclusion: CRLF2-ScFv is a selective targeting moiety for CRLF2 with a significant internalization potential and receptor antagonistic effect, highlighting the therapeutic implications for targeting Ph-like ALL. Keywords: CRLF2, ScFv, STAT5 phosphorylation, Patient-Derived Xenografts. Disclosures No relevant conflicts of interest to declare.

scholarly journals Venous thromboembolism in patients with acute leukemia: incidence, risk factors, and effect on survival

Blood ◽  
2009 ◽  
Vol 113 (17) ◽  
pp. 3911-3917 ◽  
Author(s):  
Grace H. Ku ◽  
Richard H. White ◽  
Helen K. Chew ◽  
Danielle J. Harvey ◽  
Hong Zhou ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Acute Leukemia ◽  
Lymphoblastic Leukemia ◽  
Venous Catheter ◽  
Population Based ◽  
Older Age ◽  
Myelogenous Leukemia ◽  
Vein Thrombosis ◽  
Chronic Comorbidities

Abstract A population-based cohort was used to determine the incidence and risk factors associated with development of venous thromboembolism (VTE) among Californians diagnosed with acute leukemia between 1993 to 1999. Principal outcomes were deep vein thrombosis in both the lower and upper extremities, pulmonary embolism, and mortality. Among 5394 cases with acute myelogenous leukemia (AML), the 2-year cumulative incidence of VTE was 281 (5.2%). Sixty-four percent of the VTE events occurred within 3 months of AML diagnosis. In AML patients, female sex, older age, number of chronic comorbidities, and presence of a catheter were significant predictors of development of VTE within 1 year. A diagnosis of VTE was not associated with reduced survival in AML patients. Among 2482 cases with acute lymphoblastic leukemia (ALL), the 2-year incidence of VTE in ALL was 4.5%. Risk factors for VTE were presence of a central venous catheter, older age, and number of chronic comorbidities. In the patients with ALL, development of VTE was associated with a 40% increase in the risk of dying within 1 year. The incidence of VTE in acute leukemia is appreciable, and is comparable with the incidence in many solid tumors.

Study on the Phenotype Polymorphism of CYP3A4 Gene in Chinese Children with Acute Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4376-4376
Author(s):  
Xiao-jun Yuan ◽  
Long-Jun Gu ◽  
Hui-jun Zhao ◽  
Jin-cai Zhao ◽  
Jing-Yan Tang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Acute Leukemia ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Healthy Children ◽  
Cyp3a4 Activity ◽  
Significant Difference ◽  
Average Activity ◽  
Cyp3a4 Gene ◽  
Wbc Count

Abstract In order to offer objective refering paramete for individualized chemotherapy, to clarify the distribution feature of CYP3A4 activity in Chinese children with acute leukemia and in healthy children, to explore the possible correlation between the activity of CYP3A4 gene and the predisposition or chemotherapy effect in acute leukemia children. High performance liquid chromatography (HPLC) was used to detecte the activity of CYP3A4 in 85 healthy children and 120 acute leukemia children, then analyzed the difference of phenotypebetween two groups. The activity coverage of CYP3A4 was 2.34~48.88 in healthy children and the average activity was 9.76±6.99. Among them, CYP3A4 activity was 11.88±8.88 in male group and 7.12±3.37 in female group, the former was obviously higher than the latter (P=0.0077). In less than 12-years group, CYP3A4 activity was 8.97±6.27, while it was 10.43±7.74 in more than 12-years group, there was no significant difference (P&gt;0.05). The change scope of CYP3A4 activity was very large in children with acute lymphoblastic leukemia, from 2.00 to 585.72, the average activity was 53.52, with no dfference in sex and age. According to the clinical risk degree, the activity of CYP3A4 was 4.87±2.93 in standard-risk group, it was 31.63±19.20 in middle-risk group, the latter was significantly higher thanthe former (P=0.0004). Comparison based on WBC count at the beginning of preliminary diagnosis, the CYP3A4 activity was the lowest in WBC count less than 50 x 109/L group, it was second in the group of WBC count between 50 x 109/L to 100 x 109/L, and the activity was the highest in WBC count more than 100 x 109/L group. The mean activity of CYP3A4 in childern with acute lymphoblastic leukemia with P170 less than 5% was 17.56±13.44, while it was 87.62±49.28 in those children with P170 more than 5%Ä, there was statistic difference between the two group(P=0.022). The activity in those preliminary diagnosed children with BCR-ABL(+) or Ph (+) or t (4,11) abnormal karyotype (105.86±44.41) was higher than those with normal karyotype patients (47.61±22.63), P=0.0219. Comparison the activity of CYP3A4 between those chlidren with clinical presentation as prednisone good response (PGR) and those with prednisone poor response, the activity in former group (27.23±13.58) was obviously lower than that of latter group (114.12±48.39), P=0.0358. The average CYP3A4 activity in children with acute myelocytic leukemia (AML) was 13.97±10.84. Of them, it was 15.09±7.52 in AML children with diploid chromosome and only 2.95±1.39 in hypodiploidy group, obviously, the activity of former group higher than that of latter group (P=0.0132). The CYP3A4 activity was respectively 19.78±11.59 and 2.86±1.16 in normal LDH group and in increased LDH group, there was significant difference (P=0.0036). The AML children with exo-marrow infiltration when diagnosis, their CYP3A4 activity (6.50±3.05) was lower than those children with pure marrow infiltration (19.06±11.15), P=0.044. There may be no race difference between the CYP3A4 activity of Chinese healthy children and White people. Increased CYP3A4 activity has closed correlation with ALL risk factors. The general CYP3A4 activity in AML children group was lower than that of ALL chlidren group. Much higher or much lower CYP3A4 activity may produce adverse influence to individuals.

The Retrospective Analysis of Pediatric Acute Leukemia Cases between 1980–2003: Hacettepe Experience.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4542-4542
Author(s):  
Sule Unal ◽  
Gonul Hicsonmez ◽  
Sevgi Yetgin ◽  
Aytemiz Gurgey ◽  
Fatma Gumruk ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Leukemia ◽  
Hematologic Malignancy ◽  
Lymphoblastic Leukemia ◽  
Hematologic Malignancies ◽  
Cns Involvement ◽  
Laboratory Findings ◽  
Cancer Data ◽  
Significant Difference

Abstract Leukemia constitutes 25–30% of all pediatric malignancy cases. The epidemiologic and demographic characteristics of this group of patients are important not only for determination of the prognostic factors, but also the risk factors. In this study, 683 patients under 16 years of age who were diagnosed with acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML) between January 1980-July 2003 in Hacettepe University, Pediatric Hematolgy Division are analyzed retrospectively. Besides the epidemiologic characteristics including age, sex, geographic distiribution; the type of disease, clinical presentation, physical examination and laboratory findings on admission and the survival and prognosis relationships are also evaluated in order to determine the disease properties of our country. ALL patients have recieved St. Jude Total XI until 1997, and after 1997 they are treated by St. Jude Total XIII protocol. AML patients have been treated by AML 1995 and AML 1998 protocols. The study group includes 548 (80.2%) ALL and 135 (19.8%) AML cases. Two thirds of the all acute leukemia cases are males in both ALL and AML cases. The median age at diagnosis is 62 months for ALL and 108 months for AML patients. ALL is more common among 1–5 year old group; AML is more common among adolescent age group. The incidence of hematologic malignancies increases suddenly in 1997 and 1998 and then showes a decline later. The hematologic malignancy cases who have been admitted to our clinic is most commonly living in the northern and southeastern parts of Turkey. 50% of ALL and AML patients presents with the complaints of fever and pallor. Bone pain is significantly more common in ALL patients. Median time between onset of syptoms and diagnosis is 30 days for both ALL and AML patients. Lymphadenopathy is present in almost half of ALL and AML patients at diagnosis. Hepatomegaly (72.4% vs 50.4%) and splenomegaly (53.8% vs 36.3%) are more commonly observed in ALL then AML patients (p<0.001). The central nervous system (CNS) involvement is present in 5.8% of ALL and 5.9% of AML patients. There is no statisticaly significant difference between ALL and AML patients in terms of bone, mediastinial and CNS involvements. The most common cytogenetical abnormality in ALL patients is hypodiploidy. 25.4% of ALL and 43.7% of AML patients have relapsed subsequently. The most common type of relaps is seen in bone marrow in both ALL and AML cases, however CNS relaps is seen more commonly among ALL patients (31% vs 4%). Fatality rates of ALL and AML are 20.1% and 56.3%, respectively. The fatality rate of AML is significantly higher than ALL. The CNS involvement at diagnosis and sex have no influnce on the fatality rates; on the other hand the presence of relaps for ALL and AML groups and L3 subtype, being less then 1 year old at diagnosis for ALL cases have a negative effect on fatality rates. Also the fatality rates of ALL patients who have been diagnosed before 1997 and recieved St. Jude Total XI protocol has higher fatality rates then who have been diagnosed after 1997 and recieved St. Jude Total XIII (23.3% vs 14.1%). The collection of the cancer data throughout the country is crucial for the determination of the distribution and risk factors of our country. The best way of cancer data collection is development of cancer recording systems and analyzing these data for the determination of distribution and risk factors of patients with hematologic malignancies.

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