Venous Thromboembolism in Children with Acute Lymphoblastic Leukemia in Northern Europe

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3652-3652
Author(s):  
Nadine Gretenkort Andersson ◽  
Susanna Ranta ◽  
Tony Frisk ◽  
Maria Winther Gunnes ◽  
Jon Helgestad ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Risk Treatment ◽  
The Impact ◽  
All Treatment

Abstract Introduction Children with acute lymphoblastic leukemia (ALL) are at high risk for VTE due to several thrombotic risk factors such as the disease itself, central venous line (CVL), immobilization, infections and treatment with asparaginase and steroids, leading to increased morbidity and mortality. Identifying the clinical risk factors and high risk treatment phases for VTE is important and can lead to a better outcome and quality of life for these children. We conducted this prospective study on symptomatic VTE in children with ALL to characterize the prevalence, the clinical characteristics, and potential clinical predictive factors for symptomatic VTE and the impact of thrombosis on treatment delays. Methods All patients (n=1083), age 1-18 years, diagnosed with B-cell precursor or T-cell ALL between June 2008 and July 2013 and enrolled in the NOPHO ALL 2008 treatment protocol in the Nordic countries (Denmark, Finland, Iceland, Norway and Sweden), Estonia or Lithuania were included in the study. Thrombotic events (TE) were prospectively recorded until the end of December 2013. TE was defined as objectively confirmed symptomatic TE. Main questions were: time of VTE occurrence, impact on treatment delay, type of CVL, dysfunction of the CVL, blood samples including D-dimers and thrombophilia screening, family history of TE, type and duration of antithrombotic therapy, and major bleeding during anticoagulation. Results The cumulative risk of symptomatic VTE was 6.0% (CI 95% 4.7-7.7) for children treated with the NOPHO- ALL 2008 protocol. No arterial TE was found. VTE occurred in median 80 (IQR 43-118) days in the SR and 104 (IQR 39-127) days in the IR protocol and were in majority of cases associated with asparaginase treatment (84.5%, 49/58). See figure 1 for the localization of the VTE. VTE had a high impact on the treatment in the patients. Treatment with asparaginase was shortened in half of patients with VTE and chemotherapy treatment delayed in 25%. Age ≥ 15 years and residual disease ≥ 5% after induction therapy was significantly associated with VTE in the multivariate analysis (Table 1). Conclusions Our findings indicate that Venous Thromboembolism (VTE): - is a major complication of ALL treatment - may lead to reduced intensity of the ALL treatment and subsequently possible long term impact on the EFS - risk is dependent on the patients age and residual disease after leukemia induction The possibility of identifying patients with elevated risk of VTE needs to be studied further and thromboprophylaxis for such patients during high-risk treatment phases can be considered in future ALL protocols. Table 1. Multivariate Cox regression analysis of the risk for VTE Factor HR (95% CI) P value Age category, years 1-7 8-14 15-17 Ref1.9 (1.0-3.7)6.2 (3.4-11.3) <0.000 0.044 0.000 Gender Male 1.6 (0.9-2.8) 0.074 ALL phenotype B-precursor T-cell Bilineage Ref2.3 (1.2-4.2)4.2 (1.0-17.4) 0.019 0.010 0.047 Residual disease ≥ 5% day 29 4.1 (1.9-9.0) 0.001 Figure 1. Localization of VTE Figure 1. Localization of VTE Disclosures No relevant conflicts of interest to declare.

scholarly journals Comparative Value of the Assessment of Minimal Residual Disease in Peripheral Blood at Days 8 and 15 By Flow Cytometry in Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5270-5270
Author(s):  
Marie Loosveld ◽  
Vanessa Nivaggioni ◽  
Isabelle Arnoux ◽  
Denis Bernot ◽  
Chantal Fossat ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Low Risk ◽  
The Impact ◽  
Minimal Residual

Abstract Introduction Acute lymphoblastic leukemia (ALL) is the most frequent cancer in childhood, but treatments' progress now allowsto obtain prolonged remission or curein over 90% of the patients. Consequently, therapeutic de-escalation is now an objective for future treatment protocols, providing that biomarkers allow to reliablyidentifygood responders. Among such indicators, low levels of Minimal Residual Disease (MRD) obtained early after induction chemotherapy stand out as good candidates. The latter can be investigated usingmultiparameterflow cytometry (MFC) or real-time polymerase chain reaction (RT-PCR) for immunoglobulins or T-cell receptors (IG TCR) rearrangements. In this study we report the impact on survival of two early points of peripheral blood (PB) MRD assessment by MFC at days 8 and 15 on a cohort of 125 children with B-ALL enrolled in the French FRALLE trial and compared to molecular MRD in the bone marrow (BM) at day 35. Patients and methods. The study enrolled 67 boys and 58 girls and the duration of the study allowed for a median follow up of 52,1months. Median age at diagnosis was 57 months old (range 18 to 196), 101 children were between 1 to 10 years old and 24 were older than 10. Complete blood counts (CBC) at diagnosis showed a median of 6.7x109/L leucocytes (range 0.47 - 151x109/L) and 33% blasts (range 0 to 97%). One hundred and eight children had less than 50x109/L leucocytes while 17 had higher counts. EGIL classification at diagnosis allowed to classify patients as three B-I, 94 B-II, 27 B-III and 1 B-IV. Cytogenetic analyses were performed for 118 patients who were partitioned as follows: low risk n=47, intermediate risk n=55 and high risk n=16 (Harrisson CJ et al., BJH, 2010). Eighty-three patients were in the low risk group and 42 in the high-risk group as described by the FRALLE protocol. Seven patients of the 64 tested had an IKZF1 deletion. During the duration of the study, 20 patients relapsed and 8 died. Corticosensitivitywas defined by less than 1x109/L PB blasts on day 8 andchemosensitivity by less than 5% BM blasts on day 21 on BM smears. PB MRD was assessed in MFC with a single five or ten colors tube adapted to each patient's leukemia associatedimmunophenotypeon a backbone of CD45, CD19, CD10 and CD38. Statistical analyzes examined factors impacting disease-free survival (DFS) using Log rank test and Kaplan-Meier using theMedcalc® software (Ostend, Belgium). P values <0.05 were considered significant. Results None of diagnosis features had any significant impact on DFS: age (p=0,95), risk group (p=0,17), EGIL classification (p=0,55), cytogenetics (p= 0,87), leucocyte count (p=0,36) nor IKZF1 deletion (p=0,2). Of the 125 patients, 9 were corticoresistant, 79 corticosensitive and 37 not evaluable because of less than 1x109/L leucocyte at diagnosis.Corticosensitivity had no impact on DFS (p=0,11). Conversely,chemosensitivity had a significant positive impact on DFS (p= 0,009). Day 8 PB MRD did not oultlineany significantly different DFS, whether considering detectable vs undetectable MRD (p=0.65) or MRD levels (logwisefrom >10-1 to <10-4, p=0,22). Conversely, PB MFC at day 15 appeared highly discriminant. Considering notdetectablevs detectable MRD, 4 years DFS was 91,6+3% vs. 67,6+9% p=0,0013 (Figure 1). Further refining the thresholds of MRD logwisedid not modify the significance (p=0.004; Figure 2). Indeed, DFS at 48 months was 61+15 % (n=16) for MRD >10-3, 74+11% ( n=18) for MRD <10-3->10-4 and 92+3% ( n=91) for MRD<10-4. Comparison of PB MFC MRD on day 15 with day 35 BM molecular MRD showed concordance in 72% of the cases (83 negative/negative and 7 positive/positive, 48 months DFS 94.6+2.7% and 38+20% respectively). Eight patients were negative in PB but positive in BM (DFS 62.5+17%).Twenty seven where positive in PB but negative in BM (DFS 83.5+7.6%).These differences were statistically highly significant (p <0.0001). Conclusion This study demonstrates that even in the good prognosis context of childhood ALL, early MRD retains a highly significant prognostic value. It is of importance that this result was obtained not only on day 35 BM but interestingly, even earlier on day 15 PB. This less invasive procedure can easily be applied, especially for children. It should allow to detectgood responders, with MFC MRD levels below 10-4 for whom a de-escalation of chemotherapy could be considered. Conversely, the detection of blasts by MFC in day 15 PB is worrisome. Disclosures No relevant conflicts of interest to declare.

The Development Of Venous Thromboembolism May Increase The Risk Of Osteonecrosis In Children With Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3864-3864
Author(s):  
Badhiwala H. Jetan ◽  
Trishana Nayiager ◽  
Uma H. Athale
Keyword(s):  
Risk Factors ◽  
Logistic Regression ◽  
Venous Thromboembolism ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Older Age ◽  
Regression Analyses ◽  
Female Ratio ◽  
Increased Risk ◽  
The Impact

Abstract Background Osteonecrosis (ON) is a severely disabling complication of anti-leukemic therapy, specifically long-term corticosteroid use. A hypercoagulable state is thought to underlie corticosteroid-related ON. Children with acute lymphoblastic leukemia (ALL) are also at increased risk of venous thromboembolism (VTE), indicating underlying hypercoagulability in this disease entity. Hence, we explored the relationship between ON and VTE, along with the association of ON with other variables, including age and asparaginase (ASP) therapy, in children with ALL. Methods Health records of children (< 18 yrs.) with de novo ALL treated at McMaster Children’s Hospital from 1992 to 2010 were reviewed. Patients were treated according to Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocols. Data regarding demographics, leukemia diagnosis and therapy, development and characteristics of ON and VTE, and thrombophilia work-up, if any, were collected from computer records and chart review. Osteonecrosis was diagnosed by plain X-ray, computed tomography (CT), magnetic resonance (MR) imaging, and/or technetium-99m (99mTc) bone scan. We included ON diagnosed during therapy and/or at any point during post-treatment follow-up. Standard radiological measures, including venous Doppler ultrasound and/or venography (conventional, CT, MR), confirmed VTE. We included only clinically significant thromboembolic events, defined as symptomatic VTE, or asymptomatic VTE requiring anticoagulation, developing during ALL therapy. Logistic regression analyses were performed to identify possible predictors of ON. Odds ratios (ORs) with 95% confidence intervals (CIs) and corresponding p-values were determined. Results Mean age of the study cohort (n = 208) was 5.4 years and male/female ratio 1.2:1. Seventy-eight (37.5%) patients had high-risk (HR) ALL and 127 (61.1%) received dexamethasone (DEX) as post-induction steroid. One hundred and sixty-two (77.9%) patients received E. coli ASP, 19 (9.1%) Erwinia ASP, and 27 (13.0%) PEG ASP. Twenty-one (10.1%) children developed ON. Joints affected by ON included the ankle in 11 subjects, knee in 10, hip in 8, and heel in one. Fourteen of the 21 patients (66.7%) had involvement of more than one joint. All patients were diagnosed with ON during ALL treatment, with the average being 69.2 weeks following ALL diagnosis. Forty-two (20.2%) subjects had a VTE while receiving therapy at an average of 29.4 weeks after ALL diagnosis. Nine patients had cerebral sinovenous thrombosis, 7 deep vein thrombosis (DVT), and one pulmonary embolism (PE). Twenty-six patients developed a central venous line (CVL)-related VTE. Results of univariate logistic regression analyses for osteonecrosis are presented in Table 1. VTE strongly predicted development of ON – OR 8.85 (95% CI 3.37–23.25, p< 0.001). Thirteen (31.0%) patients with VTE developed ON compared to 8 (4.8%) of 166 subjects without VTE. In 10 of 13 (76.9%) patients who developed both VTE and ON, the diagnosis of VTE preceded that of ON. Given that older age is a known risk factor for both VTE and ON, we conducted a multivariate analysis, which confirmed that age, ASP type, and VTE were independent, significant risk factors for ON (Table 2). Conclusion In addition to the known impact of older age, we identified VTE and type of ASP as independent risk factors for ON in children with ALL. These observations suggest overlap in the etiopathogenesis of ON and VTE. We recommend larger, prospective studies to confirm the association of VTE and PEG ASP with ON and to assess the impact of hypercoagulability on the development of ON. This in turn may help develop preventive strategies (e.g., thromboprophylaxis) for ALL-associated ON. Disclosures: No relevant conflicts of interest to declare.

Daratumumab for eradication of minimal residual disease in high-risk advanced relapse of T-cell/CD19/CD22-negative acute lymphoblastic leukemia

Leukemia ◽  
2019 ◽  
Vol 34 (1) ◽  
pp. 293-295 ◽  
Author(s):  
Yishai Ofran ◽  
Shimrit Ringelstein-Harlev ◽  
Ilana Slouzkey ◽  
Tsila Zuckerman ◽  
Dana Yehudai-Ofir ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Minimal Residual

scholarly journals Integrated Genomic Analyses Identify High-Risk Factors and Actionable Targets in T-Cell Acute Lymphoblastic Leukemia

2021 ◽  
Author(s):  
Haichuan Zhu ◽  
Bingjie Dong ◽  
Yingchi Zhang ◽  
Mei Wang ◽  
Jianan Rao ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Hematologic Malignancy ◽  
Lymphoblastic Leukemia ◽  
Pi3k Pathway ◽  
High Risk Factors ◽  
Genomic Analyses ◽  
Cell Acute Lymphoblastic Leukemia

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy often associated with poor outcomes. Recent unbiased genomic landscape studies have identified frequently mutated genes and dysregulated pathways in major subtypes of T-ALLs. However, few of these large-scaled genomic analyses have survival-related data, which makes molecular-based prognosis and designing new-targeted therapies difficult. To identify high-risk factors and potential actionable targets for T-ALL, we perform integrated genomic and transcriptomic analyses on samples from 165 Chinese pediatric and adult T-ALL patients, of whom 85% have outcome information. Among 47 recurrently mutated genes in 7 functional categories, we identify RAS and PI3K pathway mutations as poor survival factors for non-TAL and TAL subtypes, respectively. Mutations in the PI3K pathway are mutually exclusive with mutations in the RAS and NOTCH1 pathways, and transcription factors. Further analysis demonstrates that approximately 43% of the high-risk patients harbor at least one potential actionable alteration identified in this study, and T-ALLs with RAS pathway mutations are hypersensitive to MEKi in vitro and in vivo. Thus, our integrated genomic analyses not only systematically identify high-risk factors but suggest that these high-risk factors are promising targets for T-ALL therapies.

A Systematic Review of Blinatumomab in the Treatment of Acute Lymphoblastic Leukemia: Engaging an Old Problem With New Solutions

2021 ◽  
pp. 106002802098841
Author(s):  
Zachery Halford ◽  
Carli Coalter ◽  
Vanessa Gresham ◽  
Tabitha Brown
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
T Cell Activation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Phase Iii ◽  
Cytotoxic T Cell ◽  
Bispecific T Cell Engager

Objective: To assess the current literature for blinatumomab in the treatment of adult and pediatric B-cell acute lymphoblastic leukemia (ALL). Data Sources: We conducted a PubMed (inception to December 11, 2020) and ClinicalTrials.gov systematic literature search using the following terms: blinatumomab, Blincyto, lymphoblastic leukemia, and bispecific T-cell engager. Study Selection and Data Extraction: All relevant published articles, package inserts, and meeting abstracts evaluating the use of blinatumomab in ALL were considered for inclusion. Data Synthesis: Blinatumomab, a first-in-class bispecific T-cell engager monoclonal antibody, facilitates cytotoxic T-cell activation and subsequent eradication of CD19-positive B cells. The confirmatory phase III TOWER trial demonstrated superior overall survival (OS) with blinatumomab compared with standard chemotherapy (7.7 months vs 4.0 months) in relapsed and refractory (R/R) B-cell ALL. In the phase II BLAST trial, blinatumomab achieved a complete measurable residual disease (MRD) response in 78% of evaluable patients, with a median OS of 36.5 months. Potentially life-threatening cytokine release syndrome and neurotoxicity occurred in approximately 15% and 65% of patients, respectively. Relevance to Patient Care and Clinical Practice: Following initial Food and Drug Administration approval in 2014, blinatumomab gained expanded approval in pediatric patients and in Philadelphia chromosome-positive R/R ALL. In 2018, blinatumomab became the first and only drug approved for the treatment of persistent MRD in any hematologic malignancy. Emerging data demonstrate promising efficacy with blinatumomab in specific ALL settings, including frontline therapy, as a bridge to transplantation, and in “chemotherapy-free” combination regimens. Conclusions: Blinatumomab provides a paradigm-shifting treatment option; however, many questions surrounding optimal patient selection, sequencing, and cost-effectiveness remain.

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