Clinical Features of Children with Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis in Japan: Retrospective Nationwide Survey

Background: Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders characterized by overproduction of differentiated hematopoietic cells. Among MPNs, chronic myeloid leukemia (CML) with BCR-ABL1 is the best studied subtype and is sometimes diagnosed during childhood. "Ph-negative" MPNs are typically found in older adults and are exceedingly rare during childhood. These classical Ph-negative MPNs include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Because of this rarity, clinical features of pediatric MPNs are largely unknown, except for CML. Method: We administered questionnaires to institutions registered with the Japanese Society of Pediatric Hematology/Oncology (JSPHO). We collected clinical information of pediatric and young adult patients aged younger than 30 years who had been diagnosed with Ph-negative MPNs during 2000-2016. This study was conducted as a project of the Leukemia and Lymphoma Committee of the JSPHO. Results: We received responses from 145 institutions, which included all 107 board-certificated educational institutions of the JSPHO. A summary of the clinical features of included patients is shown in Table 1. From 2000 to 2016, 5 patients with PV, 42 with ET, and 2 with PMF were newly diagnosed with Ph-negative MPNs. Among them, 1 patient with PMF was excluded from subsequent analysis because of insufficient clinical information. The male-female ratio was almost balanced. The median age at diagnosis was 14 years for patients with PV, 9 years for patients with ET, and 1 patient with PMF was 10 months old. Only 1 patient with PV had a karyotype abnormality. The median follow-up period was 51 months since diagnosis. The JAK2V617F mutation was screened in almost all patients, and no patients with PV and 9 patients with ET had this mutation. With regard to treatment, 3 of 5 patients with PV received phlebotomy. Among patients with ET, aspirin was used most frequently (21 patients), followed by anagrelide (11 patients). However, 2 patients with PV and 8 patients with ET received no therapeutic approach. With regard to adverse events, hemorrhage and thrombosis were observed in 4 and 3 patients with ET, respectively, but these events were not found in patients with PV or PMF. Transformation to leukemia or myelofibrosis was found in 1 and 1 patient with PV, and 1 and 3 patients with ET, respectively. Among the patients who received no therapeutic approach, only 1 patient with PV experienced a hemorrhagic event and no other patients experienced any adverse events. Only 1 child with PV died owing to subsequent development of myelofibrosis and acute myeloid leukemia approximately 11 years after the initial diagnosis of PV. Conclusion: To the best of our knowledge, this is the first nationally-representative survey to clarify the clinical aspects of pediatric patients with Ph-negative MPNs. Although the methodology was not standardized, the frequency of the JAK2V617F mutation appears to be lower than that previously reported for adult patients. Moreover, the incidence of adverse events, such as thrombosis, hemorrhage, leukemia development, and transformation to myelofibrosis, was much lower than that of adult patients. As a result, although at relatively short durations of follow-up, the prognosis of pediatric patients with Ph-negative MPNs appears to be comparatively good. Further study with genetic analysis is warranted to determine the clinical and genetic features of pediatric patients with Ph-negative MPNs. Disclosures Mitsui: Astellas pharmaceutica: Research Funding; Daiichi Sankyo pharmaceutical: Research Funding; Chugai pharmaceutical: Research Funding; Teijin pharmaceutical: Research Funding; JCR pharmaceutical: Research Funding; Maruho pharmaceutical: Research Funding; MSD pharmaceutical: Research Funding; Shionogi pharmaceutical: Research Funding.

Download Full-text

Mathematical Modelling Of The Molecular BCR-ABL1 Transcript Response In Chronic Myeloid Leukemia: A Comparison Of Adult and Pediatric Patients

Blood ◽

10.1182/blood.v122.21.2709.2709 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2709-2709

Author(s):

Rick Proschmann ◽

Meinolf Suttorp ◽

Andreas Hochhaus ◽

Christian Thiede ◽

Ingo Roeder ◽

...

Keyword(s):

Mathematical Model ◽

Stem Cell ◽

Statistical Analysis ◽

Mathematical Modelling ◽

Myeloid Leukemia ◽

Research Funding ◽

Pediatric Patients ◽

Treatment Cessation ◽

Modelling Approach

Abstract Introduction Treatment of chronic myeloid leukemia (CML) with imatinib (IM) has replaced stem cell transplantation as first line therapy also in pediatric patients (pts). Although CML is rare in the first 2 decades of life, pediatric studies published recently have indicated that like in adults most pts achieve prolonged molecular response (MR). In adults it could be demonstrated that IM monotherapy induces a biphasic decline of BCR-ABL1 transcript levels, characterized by an initially steep decline (α-slope) documenting the rapid initial depletion of actively cycling BCR-ABL1–positive cells, followed by a 2nd moderate decline (β-slope), most likely indicating the slow elimination of residual leukemic stem cells (rLSK) with low turnover. In adults regular monitoring of the BCR-ABL1/ABL1 ratio during IM therapy allowed detailed mathematical modelling to predict the abundance of rLSK, which is a major determinant to access the relapse risk after treatment cessation (Horn et al, Blood 2013). A similar assessment of individual relapse risk is even more important in children because long-term IM exposure is associated with longitudinal growth retardation and may increase the risk for cardiac failure at younger age. Therefore, we sought to evaluate and adapte the existing mathematical model as established for adult German pts from the IRIS and CML IV trial to children and teenagers. Methods For statistical analysis of IM treatment response in children (trial CML-PAED-II) and adults (German arm IRIS) we required a minimal essential data set of >=7 consecutive BCR-ABL1 level measurements over at least a follow-up interval >1.5 years. Early non-responders within that interval were excluded. Data from 56 pediatric pts (male/female: 34/22; median age 12 years, range 1-18; median follow up 30.7 mos) and 60 adult pts (male/female 43/17; median age 51.5years, range 21-69, median follow up 57.4 mos) were included. For comparison of pediatric and adult cohorts a segmented linear regression model was applied to characterise the pt-specific decline of BCR-ABL1/ABL1-ratios. Five parameters were analyzed in a comparative fashion: i) the α-slope; ii) the β-slope; iii) backwards extrapolation of the α-slope (corresponding to an estimation of the BCR-ABL1 level at diagnosis); and at the breakpoint of α- and β-curves: iv) the transcript ratio as well as, v) the time point (months on IM treatment). For the corresponding modelling approach, we use an established single cell-based model of CML dynamics under IM treatment to estimate the fraction of rLSK (Roeder et al, Nat Med 2006). Results In 42/56 pediatric and in 54/60 adult pts a biphasic slope of transcript decline patterns was identified. A comparison of median response curves documented a slightly higher, however, not significant reduction of transcript ratios in the pediatric cohort with a tendency to achieve lower ratios at the breakpoint of the biphasic decline (mean BCR-ABL1 ratio adults vs pediatric: 0.103 %/ 0.051 %). This effect is attributed to a significantly increased heterogeneity in the initial IM response (SD of mean ratio adults versus pediatric: 0.63/1.2 log scales). For the α- and β-slopes no statistically significant difference was observed between the cohorts. We used the available data to adapt our mathematical model for pediatric CML, in which the slightly increased reduction in BCR-ABL1 levels in children can be attributed to an increased sensitivity to IM or an increased stem cell turnover. However, the increased heterogeneity in the initial IM response in children limits the model’s ability to provide refined risk estimators for treatment cessation and calls for the integration of further parameters. Conclusions Statistical analysis revealed distinct features of pediatric CML with respect to the dynamic response to IM treatment. In particular, we observed an increased heterogeneity in the IM response pointing towards a subgroup of pediatric pts that achieves MR4 during the initial decline (11 out of 42 children versus 2 out of 54 adults). We will further adapt our mathematical modelling approach for pediatric CML to estimate whether relapse-free treatment cessation is achieved more likely in these pts. Thereby, the model-based analysis and predictions on CML dynamics demonstrated to become useful for optimization of treatment strategies also in pediatric pts. Disclosures: Hochhaus: Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria.

Download Full-text

Transition of Care for Pediatric and Adult Patients with Venous Thromboembolism in the American Thrombosis Hemostasis Network

Blood ◽

10.1182/blood-2018-99-117533 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4711-4711

Author(s):

Madhvi Rajpurkar ◽

Maura Malone ◽

Jim Munn ◽

Julie Jaffray ◽

Crystal Watson ◽

...

Keyword(s):

Quality Improvement ◽

Venous Thromboembolism ◽

Research Funding ◽

Pediatric Patients ◽

Anticoagulation Therapy ◽

Adult Patients ◽

First Episode ◽

Transition Of Care ◽

Significant Difference

Abstract Background Venous thromboembolism (VTE) is the third leading cause of cardiovascular morbidity and mortality worldwide in adults and is increasingly seen in children. Optimal transition of care (TOC) from the inpatient to the outpatient setting may lead to improved outcomes for patients with VTE. Although several examples of TOC for patients with VTE exist, this project (ATHN 4: Transition of Care for Patients with VTE) is the first to create a uniform TOC model in the U.S that includes both pediatric and adult patients. The aim of this study was to improve the transition of care of adult and pediatric patients discharged on an anticoagulant after a first episode of VTE and evaluate patient/parent understanding and adherence to anticoagulation therapy-related instructions at seven and 30 days after hospital discharge. Methods Pediatric and adult hospitalized patients with a first episode of VTE requiring anticoagulation therapy were eligible to participate in ATHN 4, a multi-center quality improvement (QI) project conducted by the American Thrombosis and Hemostasis Network (ATHN). The project has two phases: a pre-intervention (PI) phase with no change in standard TOC practice, and a QI intervention phase consisting of enhanced education with standardized Comprehensive Discharge Instruction Modules (CDIM) for each anticoagulant. Demographics, disease, treatment characteristics, and outcomes were collected. Knowledge and feedback questionnaires were administered at 30 days post-discharge. Adult and pediatric data from the PI phase are presented. Results Complete data were submitted for 188 (91%) patients who were enrolled in the PI phase between May 2016 and March 2017 (Table 3). Results show that 73 (39%) were under 18 years of age, 90 (48%) were female, and 156 (83%) were non-Hispanic. A significant difference (p<0.001) in the location of the first VTE was noted among the pediatric and adult patients (Table 4). Approximately 66% (n=48) of the pediatric patients had a DVT, compared to 30% (n=34) of the adult patients. There were more adults with PE as compared to pediatric patients(43% vs. 3%). Adult and pediatric patients differ substantially (p <0.001) with respect to anticoagulant prescriptions. Pediatric patients were more likely to be prescribed Enoxaparin at discharge compared to adults (86% vs. 21%). Additionally, a significantly larger proportion of adult compared to pediatric patients was prescribed Warfarin (17% vs. 3%). Direct oral anticoagulants (DOACs) were mainly prescribed in the adult patients: Apixaban (24% vs. 0%) and Rivaroxaban (18% vs. 3%) compared to the pediatric patients. Based on the responses provided by the patients or guardians (for pediatric patients) during the Day 30 follow-up, there was almost an equal distribution among pediatric and adult patients who by clinical assessment were determined to have correctly taken the prescribed anticoagulant between the time of discharge and follow-up (98.6% of pediatrics and 97.4% of adults). Conclusions Our quality improvement study shows that the majority of pediatric and adult patients correctly took the anticoagulation medication prescribed to them at discharge for at least a month. Majority of pediatric patients presented with a DVT while PE was the most common presentation in adult patients. Enoxaparin and Apixaban were the most commonly prescribed anticoagulants to pediatric and adult patients, respectively. Factors affecting anticoagulation adherence and outcomes in these patients are currently being analyzed. Disclosures Rajpurkar: Bristol Myers Squibb: Research Funding; Shire: Honoraria; HEMA biologics: Honoraria; Pfizer: Honoraria, Research Funding; Novonordisk: Honoraria. Jaffray:Octapharma: Consultancy; CSL Behring: Consultancy, Research Funding; Bayer: Consultancy.

Download Full-text

Prevalence and Prognostic Significance of c-KIT Mutations in Core Binding Factor Acute Myeloid Leukemia: A Comprehensive Large-Scale Study from a Single Chinese Center

Blood ◽

10.1182/blood.v124.21.1000.1000 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1000-1000

Author(s):

Ya-Zhen Qin ◽

Honghu Zhu ◽

Qian Jiang ◽

Hao Jiang ◽

Le-Ping Zhang ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Prognostic Factors ◽

Myeloid Leukemia ◽

Large Scale ◽

Pediatric Patients ◽

Adult Patients ◽

Kit Mutation ◽

Transcript Levels ◽

Acute Myeloid

Abstract Introduction CBF-acute myeloid leukemia (AML) is a heterogeneous disease that requires prognostic factors for patient differentiation. c-KIT mutations are predominantly detected in CBF-AML among AML cases, and reported frequencies vary significantly. To date, the clinical significance of c-KIT mutations in CBF-AML has been intensively studied; however, the results are controversial and a final conclusion has not been reached. Large-scale studies with subgroup analysis should be performed to elucidate the clinical effects of c-KIT mutations in CBF-AML. Methods A total of 351 patients with CBF-AML [t(8;21) (n = 253) or inv(16) (n = 98)] were included in this study. Overall, 250 patients [42 pediatric t(8;21);146 adult t(8;21); 11 pediatric inv (16) and 51 adult inv (16)] received standard treatment and underwent follow up. Induction therapy consisted of one or two cycles of combined anthracycline and cytarabine for adult patients, whereas cytarabine, idarubicin, and etoposide were used for pediatric patients. 131, 17, and 93 of the patients further received intermediate-dose cytarabine-based chemotherapy, chemotherapy with auto-hematopoietic stem cell transplantation (HSCT), and chemotherapy with allogeneic (allo)-HSCT for consolidation, respectively. c-KIT mutations in exon 8 and 17 were screened by direct sequencing. Patients who received allo-HSCT were censored at the time of transplantation for relapse and survival analysis to exclude the effects of allo-HSCT on outcome. The median follow up time was 10 months (3 to 93 months) for the 211 living patients. Results Overall, 36.5% (128/351) of the patients were found to have a c-KIT mutation. The frequencies of c-KIT mutations were similar between pediatric and adult patients with t(8;21) AML (41.7% vs. 38.5%, P > 0.05), whereas pediatric patients tended to have higher frequency of c-KIT mutations than the adult patients with inv(16) AML (53.8% vs 25.9%, P = 0.053). In adults, the frequency of c-KIT mutations was significantly higher in patients with t (8;21) than those with inv(16) (P = 0.043). In adults, the frequency of mutations in exon 17 was significantly higher in t(8;21) than inv(16) AML (P < 0.0001). In pediatric group, the frequencies of mutations in exon 17 and exon 8 were similar for t(8;21) and inv(16) AML (P > 0.05). The low PLT count (¡Ü 30∙109/L) in pediatric t(8;21) AML tended to be associated with the presence of c-KIT mutations ( P = 0.063). High white blood cell (WBC) count (>10∙109/L), WBC index, and AML1-ETO transcript levels in adult t(8;21) AML patients were significantly correlated with the presence of c-KIT mutations (P = 0.015, 0.0051, and 0.030, respectively). Moreover, low CBF¦Â-MYH11 transcript levels in adult inv(16) AML tended to be significantly related to c-KIT mutations (P = 0.059). No difference was observed in CR rates between patients with and without c-KIT mutations (P > 0.05). c-KIT mutations were significantly associated with less reduction in fusion transcript levels after the first induction therapy in adult inv(16) patients (P = 0.021). c-KIT mutations in adult t(8;21) AML patients (n = 137) significantly correlated with higher CIR rates at 2 years and low 2-year DFS and OS rates (73.2% vs. 46.2%, P = 0.0070; 26.8% vs. 49.1%, P = 0.013; 48.9% vs. 65.7%, P = 0.0055, respectively. Figure 1). In contrast, c-KIT mutations had no impact on CIR, DFS, and OS rates in pediatric t(8; 21)(n = 42), as well as in adult inv (16) (n = 51; all P > 0.05. Figure 1). Multivariate analysis demonstrated that c-KIT mutation was the only independent prognostic factor for relapse (hazard ratio (HR) = 2.47, 95% CI = 1.25 to 4.86, P = 0.009) and DFS (HR = 2.23, 95% CI = 1.17 to 4.41, P = 0.016). Moreover, c-KIT mutation and PLT count were independent prognostic factors for OS (HR = 3.68, 95% CI = 1.57 to 8.63, P = 0.003; HR = 0.37, 95% CI = 0.16 to 0.87, P = 0.023). Conclusion CBF-AML is a heterogeneous disease with regard to c-KIT mutations. c-KIT mutations have a strong adverse impact on relapse and survival in adult t(8;21) AML. Grant support Nature Science Foundation of China (81170483 and 81370639) and Beijing Municipal Science & Technology Commission£¨Z141100000214011). Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Quality-Adjusted Survival for Low-Dose Cytarabine (LDAC) Versus Glasdegib+LDAC Among Newly Diagnosed Acute Myeloid Leukemia Patients Who Are Not Candidates for Intensive Chemotherapy: A Q-TWiST Analysis

Blood ◽

10.1182/blood-2019-126672 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2610-2610 ◽

Cited By ~ 1

Author(s):

Youngmin Kwon ◽

Timothy J Bell ◽

Caitlyn Solem ◽

Joseph C Cappelleri ◽

Courtney Johnson ◽

...

Keyword(s):

Adverse Events ◽

Myeloid Leukemia ◽

Research Funding ◽

Newly Diagnosed ◽

Employment Equity ◽

Equity Ownership ◽

Relative Gains ◽

Mean Time ◽

Low Dose Cytarabine

Introduction: The efficacy and safety of glasdegib (a selective oral inhibitor of hedgehog signaling pathway) in combination with low-dose cytarabine (LDAC) was evaluated in a randomized, phase 2 trial of newly diagnosed acute myeloid leukemia (AML) patients (BRIGHT AML 1003; NCT01546038). Patients receiving glasdegib+LDAC experienced statistically significant and meaningful gains in overall survival (OS) compared with patients receiving LDAC alone (median OS [95% CI]): 8.3 months [4.7-12.2] vs 4.3 months [1.9-5.7]). This analysis examined whether quality-adjusted survival improvements were similarly observed using a quality-adjusted time without symptoms of disease progression or toxicities (Q-TWiST) approach to evaluate possible trade-offs between time with adverse events (toxicities), time in relapse/progression (i.e., with symptoms of disease), and 'good' survival (i.e., time without toxicities or symptoms of progression [TWiST]) when comparing regimens. Methods: OS in BRIGHT AML 1003 data, restricted to a follow-up of 20 months, was partitioned into time with toxicity (TOX: grade 3+ adverse events prior to progression), TWiST, and time post-progression (REL). Progression was defined as treatment discontinuation due to insufficient clinical response or death; patients who discontinued for other reasons (including adverse events) were censored at the date of discontinuation unless death occurred within 28 days of discontinuation. Q-TWiST was calculated by multiplying restricted mean time in each state by respective utilities (U) and then summing up the utility-adjusted time. Base case analysis used U(TOX)=U(REL)=0.5 and U(TWiST)=1.0; threshold analyses were performed varying U(TOX) and U(REL) jointly each from 0 to 1. Relative gains in Q-TWiST (i.e., Q-TWiST difference (combination vs LDAC) / OS in LDAC arm) of ≥15% were considered clearly clinically meaningful per the clinical literature. Sensitivity analysis varied the length of follow-up and AE definitions; subgroup analyses were also performed. 95% confidence intervals were obtained using the bootstrap procedure. Results: At 20 months of follow-up, the survival rate for glasdegib+LDAC and LDAC arm was 28.2% and 7.9%, respectively. Glasdegib+LDAC patients (n=78) compared with LDAC patients (n=38) had significantly longer mean time in TWiST (+3.4 [95% confidence interval: 1.8, 5.2] months) and TOX (+0.8 [0.1, 1.6] months), and longer but non-significant REL (+0.3 [-1.9, 2.3] months). Q-TWiST was 4.0 [2.1, 5.8] months longer for glasdegib+LDAC, translating into a 75% relative improvement in quality-adjusted survival relative to LDAC alone. In threshold analyses, absolute and relative Q-TWiST gains ranged from 3.5 to 4.5 months and 66% to 85%, respectively (Table 1). They exceeded the clinically meaningful threshold for gains in Q-TWiST and were statistically significant across all combinations of U(TOX) and U(REL). Results were robust to length of follow-up 6 to 24 month and remained significant when including all adverse events regardless of grade. Discussions/Conclusions: Glasdegib+LDAC is an add-on therapy that has demonstrated significant survival benefits for newly diagnosed AML patients who are unable to receive intensive chemotherapy. While patients can experience a longer time with toxicities from receiving glasdegib+LDAC (as expected since it is given as an add-on therapy), the trade-off can still be favorable as the treatment provides added time spent in 'good' health (i.e., a significantly longer time in TWiST). In the BRIGHT AML 1003 cohort, the relative gains in OS greatly exceeded previously established thresholds for being clearly clinically meaningful, which suggests that the benefits of glasdegib+LDAC vs LDAC alone outweigh the risks. Table 1 Disclosures Kwon: Pfizer Inc.: Research Funding; Pharmerit International: Employment. Bell:Pfizer Inc.: Employment, Equity Ownership. Solem:Pharmerit International: Employment; Pfizer Inc.: Research Funding. Cappelleri:Pfizer: Employment, Equity Ownership. Johnson:Pfizer Inc.: Research Funding; Pharmerit International: Employment. Bhattacharyya:Pfizer Inc: Employment, Equity Ownership. Hoang:Pfizer Inc.: Employment, Equity Ownership. Cortes:Novartis: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; BiolineRx: Consultancy; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Sun Pharma: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.

Download Full-text

Failures and Successes in Pediatric Patients with Acute Myeloid Leukemia with First Relapse: A Large International Report on Current Treatment Strategies and Outcome

Blood ◽

10.1182/blood-2020-141774 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 6-7

Author(s):

Mareike Rasche ◽

Martin Zimmermann ◽

Emma Steidel ◽

Todd A. Alonzo ◽

Richard Aplenc ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Pediatric Patients ◽

Advisory Committees ◽

First Relapse ◽

Pediatric Aml ◽

Acute Myeloid

BACKGROUND: Children with high risk acute myeloid leukemia (AML) still experience consistently high rates of relapse. Survival after first relapse increased from 21% between 1987 and 1997 up to 39% in recent studies. However, since 2009, there have been no publications on subsequent large pediatric AML relapse trials. As the indications for HSCT during first-line treatment have been extended since then, the current survival of these patients at relapse remains unclear. Herein, we report outcome results from the BFM and COG study group, which represents the largest available dataset analyzed for post-relapse survival. PATIENTS AND METHODS: Pediatric patients with first relapse of AML (no Down syndrome, secondary leukemia or FAB M3) have been analyzed from two large study groups with patients from the United States, Canada, Australia, New Zealand, Germany, Austria, Czech Republic and Switzerland. Out of 1222 patients in the BFM cohort (AML-BFM study 2004, registry 2012 and study 2012), 350 experienced at least one relapse and 197 of those had a first relapse after closure of the last I-BFM relapse trial (04/2009 through 2017). Within the Children's Oncology Group (COG) Phase 3 trials (AAML0531 and AAML1031, n=2119) 852 pediatric patients suffered a relapse. Five-year probability of overall survival (pOS) and event-free survival (pEFS) were calculated according to Kaplan-Meier. EFS was calculated for the BFM cohort as time from relapse to the next event (second relapse, death, failure to achieve a second remission or secondary malignancy) or until last follow-up, while OS reflects the time from relapse until death or last follow-up. The Cox proportional hazards model was used for multivariate analysis of outcomes. Living patients were censored at last follow-up with a median follow-up after relapse of 4·2 years (BFM) and 4·8 years (COG). Data have been frozen at 03/27/2020 (BFM) and 03/31/2020 (COG). RESULTS: In the 197 patients with relapse after closure of the last BFM relapse trial (04/2009 through 2017) the pOS at 5 years was 42±4% (BFM). The 5-year pOS in patients relapsing after COG trials 2006-2018 was 35±2% (n=852). Patients experiencing a relapse between 2014 to 2017 had a pOS of 49±6% (BFM, n=78) and 40±3% (COG, n=333). Risk classification at initial diagnosis and a short time from diagnosis to relapse predicted a diminished survival probability in both cohorts (see Table 1). However, the absence of full hematopoietic regeneration of the bone marrow after re-induction did not predict survival: Within the BFM dataset, a subgroup analysis in all patients receiving DNX-FLA (n=156) have been performed. Initial characteristics are comparable to the total cohort. Among these patients 147 were evaluable for response (7 excluded due to early death before evaluation, 2 for insufficient data). Eighty-nine (57%) achieved a CR (n=69) or CRp (n=20) and 52 (33%) no response. Overall survival was superior for patients with a CR/CRp (54±6% (CR/CRp) vs. 32±7% (No CR/CRp); p=0·0064), but long-term survival was still possible even with a poor re-induction response. Patients with a CRp had a comparable survival to those with a CR after a second re-induction (pOS 60±11% (CRp) vs. pOS 52±7% (CR); p=0·57). Patients with >5% leukemic blasts (n=32) had the lowest survival (pOS 27±9%). The 5-year pEFS for this cohort was 29±4% (pEFS 50±6% (CR) vs. pEFS 50±11% (CRp)). The analysis of post-relapse treatment showed that the vast majority of patients who survive had a HSCT following relapse. By landmark analysis, survival was significantly higher in patients with subsequent HSCT compared to that of non-transplanted patients (BFM: pOS 53±4%, n=154 vs. pOS 5±5%, n=21; p(Mantel-Byar)=0·0002). CONCLUSION: This is the largest report to date on post relapse survival in children with AML. Our analysis confirmed previously described risk factors for poor survival while also highlighting new findings contrary to established standards. Strikingly, the absence of full hematopoietic regeneration of the bone marrow after re-induction did not predict survival at first relapse, thereby questioning the current value of the established International Working Group Criteria published by Cheson et al for response-evaluation in pediatric AML. As the international pediatric AML community embarks on collaborative efforts to evaluate new therapies in children with relapsed AML, a comprehensive review of post relapse survival is critical. Disclosures Bourquin: Servier: Other: Travel Support. Reinhardt:Novartis: Membership on an entity's Board of Directors or advisory committees; CLS Behring: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Safety and Efficacy of Bosutinib in Fourth Line Therapy of Chronic Myeloid Leukemia Patients

Blood ◽

10.1182/blood.v126.23.2786.2786 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2786-2786

Author(s):

Valentín García-Gutiérrez ◽

Dragana Milojkovic ◽

María Luisa Martín Mateos ◽

Simone Claudiani ◽

Concepcion Boque ◽

...

Keyword(s):

Pleural Effusion ◽

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Myeloid Leukemia ◽

Research Funding ◽

Line Treatment ◽

Free Survival ◽

Safety And Efficacy ◽

Line Therapy

Abstract BACKGROUND: Despite the excellent prognostic of chronic myeloid leukemia (CML) patients since the introduction of tyrosine kinase inhibitors (TKIs), approximately 50% of patients that are treated with TKIs will discontinue first line treatment due to lack of efficacy or intolerance. Once patients need a second line treatment, a considerable proportion of patients will need third or even fourth line therapy during further evolution. At this moment, there is a lack of data about real benefit of this group of patients. We have recently published our experience of 30 CML patients treated with bosutinib in 4th line. We present an update of the study where we have increased the number of patients, and the follow-up. The aim of this study is to present safety and efficacy data CML chronic phase patients treated with bosutinib in 4th line. METHODS: We have collected data from 59 CML patients treated with bosutinib in 4th line after resistance or intolerance to IM, NI and DA. 51 patients have been treated under the Spanish compassionate use program (36 centers) and 10 patients were treated in a single institution from United Kingdom. Median age of patients at diagnosis was 53 years. The percentage of low, intermediate and high risk Sokal groups were 47%, 37% and 16%. Median time TKIs exposure before bosutinib was 9 years. The most common indication (30/59) was intolerant to DA and NI. Patients' dispositions and main line characteristics are shown in table 1. RESULTS: Median follow-up was 14.3 months. All patients started bosutinib at 500mg/d, median dose of was 450mg/d. Overall probabilities to either achieve or maintain previous response were 96% (57/59), 62% (37/59), 40% (24/59) and 17% (10/59) for complete hematological response (CHR), complete cytogenetic response (CCyR), major molecular response (MMR) and MR4.5 respectively. However, probabilities to obtain responses (in patients without response evaluated at baseline) were 27% (7/26), 26% (12/45) and 12% (7/55) for CCyR, MMR and MR4.5. As expected, probabilities to obtain CCyR were lower for patients resistant to DA and NI patients than for patients intolerant to DA and NI (8% VS 44%). Event free survival (EFS) and progression free survival (PFS) probabilities were 50% and 83% by 27 month. Treatment was discontinued in 20/58 (34%), most frequent reasons being adverse events 9/59(15%), lack of efficacy 5/59 (8.5%), disease progression 2/59 (3.4%) and death 1/59 (1.7%). Two patients discontinued due to stem cell transplantation. The adverse events that led to treatment discontinuation were pleural effusion (3), diarrhea (2), rash, renal impairment, auricular fibrillation and liver enzyme elevation one patient each. Overall, bosutinib was well tolerated. Grade 3-4 hematological toxicities were 3%, 6% and 6% for anemia, thromboctytopenia and neutropenia. Most common non hematological side effects were diarrhea (39%, nauseas 13% and liver alterations 14% and pleural effusion 14%. CONCLUSIONS: Little is known about the therapeutic role of Bosutinib in 4th line. The series presented here is, to our knowledge, the largest being presented. Bosutinib seems to be an appropriate treatment option for patients resistant or intolerant to three prior TKIs. Table 1. IM+NI-I+DA-R (N=4) IM+NI-R+DA-R (N=18) IM+NI-I+DA-I (N=30) IM+NI-R+DA-I (N=7) Total (N=59) Sex, N (%) Male 2 (50) 11 (61.1) 16 (53.3) 2 (28.6) 31 (52.5) Median age of diagnosis, yr (range) 57.32 (50-64) 49.19 (23-73) 54.95 (21-89) 48.87 (26-68) 53.15 (21-89) Median age of Bosutinib initiation, yr (range) 69.13 (61-70) 62.27 (39-79) 64.85 (25-90) 64.79(35-74) 63.7 (25-9) Median follow up, months (range) 18.5(7.8-34.1) 8.4(1.22-36.1) 16.3(0.5-34.7) 23.4(3.3-28.9) 14.3(0.7-36.1) SOKAL Index at diagnosis, N (%) High 2(50.0) 4 (23.5) 1 (4.3) 1 (20) 8 (16.3) Intermediate 1 (25.0) 5 (29.4) 10(43.5) 2 (40) 18 (36.7) Low 1 (25.0) 8 (47.1) 12 (52.2) 2 (40) 23 (46.9) Median Time from first TKI to BOS, (yr, range) 10.3 (4.8-11.9) 9.3 (2.0-11.4) 8.8 (0.7-13.6) 8.2 (5.1-12.3) 8.8 (0.7-13.6) Median duration of prior therapy, months (range) Imatinib 38.8 (11.8-69.8) 32.6 (6.3-96.8) 26.2 (1.6-102.6) 23.1 (8.3-66.8) 28.8 (1.6-102.6) Dasatinib 21.5 (12.6-75) 21.8 (7.7-69) 31.4 (0.4-87.1) 23.7 (10.3-53.6) 23.44 (0.4-87.1) Nilotinib 19.1 (2.1-46.2) 16.7 (5-65.6) 8.9 (0.2-58.5) 30.9 (6.9-49.3) 14.3 (0.2-65.6) BOS: bosutinib, IM, imatinib; DA, dasatinib; NI, nilotinib, I: Intolerance, R: Resistant, Yr: year Disclosures García-Gutiérrez: Ariad: Consultancy; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Milojkovic:Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Boque:Novartis: Honoraria; BMS: Honoraria; Celgene: Honoraria. Casado:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Jiménez:Pfizer: Consultancy, Honoraria. Giraldo:Pfizer: Consultancy. Steegmann:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Download Full-text

POS0815 CLINICAL CHARACTERISTICS, IMAGING PHENOTYPE, AND LONG-TERM OUTCOMES OF TAKAYASU ARTERITIS PATIENTS WITH HYPERTENSION

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.3494 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 661.1-661

Author(s):

Y. Sun ◽

L. Ma ◽

H. Chen ◽

C. Rongyi ◽

L. Jiang

Keyword(s):

Blood Pressure ◽

Adverse Events ◽

Clinical Features ◽

Takayasu Arteritis ◽

Pressure Control ◽

Free Survival ◽

The World ◽

Cluster 2

Background:Hypertension occurred in 30-80% of TAK patients around the world. The occurrence of hypertension might severely worsen TAK prognosis. Nevertheless, data describing the specific imaging features in hypertensive TAK patients and the associations between hypertensive severity, blood pressure control status and long-term outcome were still lacking.Objectives:To investigate the characteristics and associations of hypertensive characteristics with adverse events-free survival in Takayasu arteritis (TAK) patients with hypertension.Methods:This research was based on a prospectively on-going observational cohort-East China Takayasu Arteritis (ECTA) cohort. In all, 618 TAK patients, who registered in the ECTA cohort up to December 2019, were enrolled. The main outcome was the adverse-events-free survival among hypertensive TAK patients during the follow-up ended on August 2020.Results:Totally, 204 (33.0%) patients suffered from hypertension, with 48 (23.5%), 62 (30.4%), and 94 (46.1%) mild, moderate, and severe hypertension, respectively. Cluster analysis indicated three imaging phenotypes for hypertensive TAK patients: Cluster 1: involvement of the abdominal aorta and/or renal artery (n=56, 27.5%); Cluster 2: involvement of the ascending aorta, thoracic aorta, and the aortic arch and its branches (n=38, 18.6%); Cluster 3: combined involvement of Cluster 1 and Cluster 2 (n=111, 54.4%). By the end of the follow-up, the blood pressure control rate was 50.8%, while the adverse-events-free survival was 67.9% in the entire hypertensive population. Multivariate Cox regression analysis indicated that well-controlled blood pressure (HR=2.13, 95%CI 1.32–3.78, p=0.047), co-existence of severe aortic valve regurgitation (HR=0.87, 95%CI 0.64–0.95, p=0.043), Cluster 1 (HR=0.69, 95%CI 0.48–0.92, p=0.017) and Cluster 3 (HR=0.72, 95%CI 0.43–0.94, p=0.048) imaging phenotype was associated with the adverse-events-free survival.Conclusion:Patients with controlled hypertension showed better adverse-events-free survival, while those with the Cluster 1 imaging phenotype were more likely to suffer from worse adverse-events-free survival. Hypertension occurred in 30-80% of TAK patients around the world. The occurrence of hypertension might severely worsen TAK prognosis.References:[1]Johnston SL, Lock RJ, Gompels MM. Takayasu arteritis: a review. J Clin Pathol 2002; 55:481–6.[2]Watanabe Y, Miyata T, Tanemoto K. Current clinical features of new patients with Takayasu arteritis observed from a cross-country research in Japan: age and sex specificity. Circulation 2015; 132:1701–9.[3]Yilmaz N, Can M, Oner FA, et al. Impaired quality of life, disability and mental health in Takayasu’s arteritis. Rheumatol. (Oxford) 2013; 52:1898–904.[4]Laurent A, Julien H, Nicolas L, et al. Takayasu arteritis in France: a single-center retrospective study of 82 cases comparing white, North African, and black patients. Medicine 2010; 89:1–17.[5]Mwipatayi BP, Jeffery PC, Beningfield SJ, et al. Takayasu arteritis: clinical features and management: report of 272 cases. ANZ J Surg 2005; 75:110–7.Disclosure of Interests:None declared

Download Full-text

Myeloid Sarcoma Involving the Breast

Archives of Pathology & Laboratory Medicine ◽

10.5858/2005-129-32-msitb ◽

2005 ◽

Vol 129 (1) ◽

pp. 32-38 ◽

Cited By ~ 2

Author(s):

Jose R. Valbuena ◽

Joan H. Admirand ◽

Gabriela Gualco ◽

L. Jeffrey Medeiros

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Subsequent Development ◽

Clinical Information ◽

Myeloid Sarcoma ◽

T Cell Antigens ◽

Well Differentiated ◽

Immunohistochemical Studies ◽

Acute Myeloid

Abstract Context.—Myeloid sarcoma is a neoplasm of myeloid cells that can arise before, concurrent with, or following acute myeloid leukemia. Rarely, it can also occur as an isolated mass. Objective.—To describe the clinicopathologic features of 6 patients with myeloid sarcoma involving the breast. Design.—Clinical information for all 6 patients was obtained from the medical record. Routine hematoxylin-eosin–stained slides; naphthol AS-D chloroacetate stain; and immunohistochemical stains for myeloid, B-cell, and T-cell antigens were prepared. Results.—There were 6 women with a median age of 52 years (range, 31–73 years). Two patients presented with isolated tumors of the breast, with no history or subsequent development of acute myeloid leukemia. In 3 patients, the breast tumors represented relapse of acute myeloid leukemia. One patient who presented initially with myeloid sarcoma involving the breast, skin, and spleen was lost to follow-up. Histologically, these tumors were classified as well differentiated (n = 3), poorly differentiated (n = 2), and blastic (n = 1). Naphthol AS-D chloroacetate esterase was positive in all 3 cases assessed. Immunohistochemistry showed that myeloperoxidase (n = 5) and CD43 (n = 3) were positive, and CD3 (n = 5) and CD20 (n = 5) were negative in all cases assessed. Lysozyme was positive in 4 (80%) of 5; CD117 was positive in 2 (67%) of 3; and single cases were positive for CD45 (1/3), TdT (1/2), CD79a, and the PAX5 gene product. Conclusions.—Myeloid sarcoma involving the breast is uncommon. In the literature, as in this study, these tumors most often represent relapse or the initial presentation of acute myeloid leukemia. However, 2 of the cases we report presented with isolated masses, without a history or subsequent development of acute myeloid leukemia at last follow-up. Immunohistochemical studies are extremely helpful for recognizing isolated myeloid sarcoma.

Download Full-text

Mini- Vs. Regular-Dose CLAG-M (Cladribine, Cytarabine, G-CSF, and Mitoxantrone) in Medically Less Fit Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) and Other High-Grade Myeloid Neoplasms

Blood ◽

10.1182/blood-2019-123542 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1364-1364 ◽

Cited By ~ 1

Author(s):

Anna B. Halpern ◽

Megan Othus ◽

Kelda Gardner ◽

Genevieve Alcorn ◽

Mary-Elizabeth M. Percival ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Intensive Therapy ◽

Treatment Intensity ◽

High Grade ◽

Intensive Chemotherapy ◽

Myeloid Neoplasms ◽

Acute Myeloid

Background: Optimal treatment for medically less fit adults with acute myeloid leukemia (AML) remains uncertain. Retrospective data suggest intensive therapy may lead to better outcomes in these patients. However, these findings must be interpreted cautiously because of the possibility of selection bias and other confounders. Ideally, the optimal treatment intensity is defined via randomized trial but whether patients and their physicians are amenable to such a study is unknown. We therefore designed a trial (NCT03012672) to 1) evaluate the feasibility of randomization between intensive and non-intensive therapy in this population and 2) examine the impact of treatment intensity on response rate and survival. We used CLAG-M as high-dose cytarabine-based intensive induction therapy. Rather than selecting different classes of drugs in the 2 treatment arms- which may have different modes of action and therefore confound the question of treatment intensity - we used reduced-dose ("mini") CLAG-M as the non-intensive comparator. Methods: Adults ≥18 years were eligible if they had untreated AML or high-grade myeloid neoplasms (≥10% blasts in blood or marrow) and were medically less fit as defined by having a "treatment related mortality" (TRM) score of ≥13.1, corresponding to a >10-15% 28-day mortality with intensive chemotherapy. Left ventricular ejection fraction ≤45% was the only organ function exclusion. Patient-physician pairs were first asked if they were amenable to randomized treatment allocation. If so, they were randomized 1:1 to mini- vs. regular-dose CLAG-M. If not, in order to evaluate our secondary endpoints, the patient or physician could choose the treatment arm and still enroll on study. Patients and physicians then completed surveys elucidating their decision-making processes. Up to 2 induction courses were given with mini- vs. regular-dose CLAG-M: cladribine 2 or 5 mg/m2/day (days 1-5), cytarabine 100 or 2,000 mg/m2/day (days 1-5), G-CSF 300 or 480µcg/day for weight </≥76kg in both arms (days 0-5), and mitoxantrone 6 or 18 mg/m2/day (days 1-3). CLAG at identical doses was used for post-remission therapy for up to 4 (regular-dose CLAG) or 12 (mini-CLAG) cycles. The primary endpoint was feasibility of randomization, defined as ≥26/50 of patient-physician pairs agreeing to randomization. Secondary outcomes included rate of complete remission (CR) negative for measurable ("minimal") residual disease (MRD), rate of CR plus CR with incomplete hematologic recovery (CR+CRi), and overall survival (OS). Results: This trial enrolled 33 patients. Only 3 (9%) patient/physician pairs agreed to randomization and thus randomization was deemed infeasible (primary endpoint). Eighteen pairs chose mini-CLAG-M and 12 regular-dose CLAG-M for a total of 19 subjects in the lower dose and 14 subjects in the higher dose arms. The decision favoring lower dose treatment was made largely by the physician in 5/18 (28%) cases, the patient in 11/18 (61%) cases and both in 2/18 (11%). The decision favoring the higher dose arm was made by the patient in most cases 9/12 (75%), both physician and patient in 2/12 (16%) and the physician in only 1/12 (8%) cases. Despite the limitations of lack of randomization, patients' baseline characteristics were well balanced with regard to age, performance status, TRM score, lab values and cytogenetic/mutational risk categories (Table 1). One patient was not yet evaluable for response or TRM at data cutoff. Rates of MRDneg CR were comparable: 6/19 (32%) in the lower and 3/14 (21%) in the higher dose groups (p=0.70). CR+CRi rates were also similar in both arms (43% vs. 56% in lower vs. higher dose arms; p=0.47). Three (16%) patients experienced early death in the lower dose arm vs. 1 (7%) in the higher dose arm (p=0.43). With a median follow up of 4.2 months, there was no survival difference between the two groups (median OS of 6.1 months in the lower vs. 4.7 months in the higher dose arm; p=0.81; Figure 1). Conclusions: Randomization of medically unfit patients to lower- vs. higher-intensity therapy was not feasible, and physicians rarely chose higher intensity therapy in this patient group. Acknowledging the limitation of short follow-up time and small sample size, our trial did not identify significant differences in outcomes between intensive and non-intensive chemotherapy. Analysis of differences in QOL and healthcare resource utilization between groups is ongoing. Disclosures Halpern: Pfizer Pharmaceuticals: Research Funding; Bayer Pharmaceuticals: Research Funding. Othus:Celgene: Other: Data Safety and Monitoring Committee. Gardner:Abbvie: Speakers Bureau. Percival:Genentech: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc.: Research Funding; Nohla Therapeutics: Research Funding. Scott:Incyte: Consultancy; Novartis: Consultancy; Agios: Consultancy; Celgene: Consultancy. Becker:AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; Accordant Health Services/Caremark: Consultancy; The France Foundation: Honoraria. Oehler:Pfizer Inc.: Research Funding; Blueprint Medicines: Consultancy. Walter:BioLineRx: Consultancy; Astellas: Consultancy; Argenx BVBA: Consultancy; BiVictriX: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Seattle Genetics: Research Funding; Race Oncology: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding. OffLabel Disclosure: Cladribine is FDA-approved for Hairy Cell Leukemia. Here we describe its use for AML, where is is also widely used with prior publications supporting its use

Download Full-text

Metabolomics Profile of Patients with Chronic Myeloid Leukemia and Cardiovascular Adverse Events after Treatment with Tyrosine Kinase Inhibitors

Blood ◽

10.1182/blood-2019-124323 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4144-4144

Author(s):

Giovanni Caocci ◽

Martino Deidda ◽

Antonio Noto ◽

Christian Cadeddu ◽

Marianna Greco ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Dissecting Aneurysm ◽

Metabolomic Profile ◽

The Mean

Background. Cardiovascular adverse events (CV-AE) are emerging complications in chronic myeloid leukemia (CML) patients treated with second and third generation tyrosine kinase inhibitors (TKIs). Despite the importance of CV risk factors,predictive CV-AE biomarkers are still lacking. Further understanding of the molecular pathways underlying CV-AE may promote novel strategies to prevent its initiation prior to clinical disease. In this scenario, the use of a novel tool such as metabolomics may be useful for the identification of new metabolic pathways related to CV-AE. Metabolites are the output of cellular metabolism, accounting for expression and activity of genes, transcripts, and proteins, and offering unique insights into small molecule regulation. For the first time we evaluated the correlation between CV-AE and metabolomic profile in CML patients treated with TKIs. Methods. We considered 39 adult CP-CML patients (mean age 49, range 24-70), without comorbidity at baseline, consecutively diagnosed and treated with imatinib, dasatinib nilotinib and ponatinib, at the Haematology Unit of "Businco Hospital", Cagliari, Italy. All patients underwent a metabolomic profile detection, after CV-AE or during follow-up, and were stratified in 2 groups (with or without CV-AE). Plasma samples were collected and acquired chromatogram was analysed by means of the free software AMDIS (Automated Mass Spectral Deconvolution and Identification System; http://chemdata.nist.gov/mass-spc/amdis) that identified each peak by comparison of the relative mass spectra and the retention times with those stored in an in-house made library comprising 255 metabolites. Data were investigated by applying the supervised multivariate statistical approach OPLS-DA (Orthogonal partial least square discriminant analysis) (SIMCA, version 13.0, Umetrics, Umea, Sweden). Results. The mean follow-up since CML diagnosis was 3.7 years (range 0.9-5); 22 (56.4%) patients were treated frontline, while 17 (43.5%) underwent second or subsequent TKI lines of treatments. The reason for switching was inefficacy in 15.3% and intolerance in 28.2%. At CV-AE or last follow-up 16 (41%) patients were treated with imatinib, 8 (20.5%) with dasatinib, 14 (35.8%) with nilotinib and 1 patient with ponatinib (2.7%). Overall, 17 CV-AE were recorded: 7 cases of hypercholesterolemia, 5 pleural or pericardial effusions, one episode of hypertension and 4 cardiac events (atrial fibrillation,ST-segment elevation myocardial infarction, reduction of cardiac ejection fraction and dissecting aneurysm of the aorta); 7 CV-AE were graded as 3 according to the common toxicity criteria and one patient died from dissecting aneurysm of the aorta). The 60-month cumulative CV-AE incidence was 54.4±9.1%. The mean time between the start of the treatment and the occurrence of a CV-AE was 44.4 months (range 19-60). OPLS-DA showed that patient's samples were clearly separated into 2 groups indicating that CV-AE patients (blue dots) presented a markedly distinct metabolic profile compared with patients without CV-AE (green dots); (figure 1). The parameters of the model were R2Y = 0.76 and Q2 = 0.44. To validate the OPLS-DA model, a permutation was performed resulting statistically significant (p=0,002). The main discriminant metabolites were tyrosine, lysine, ornithine, glutamic acid, 2-piperdincarboxylic acid, proline, citric acid, phenylalanine, mannitol, threonine, leucine, creatine, serine, 4-hydroxyproline, and alanine (more represented in CV-AE group); while unknown 204, myristic acid, arabitol, oxalic acid, 4-deoxyrithronic acid, elaidic acid and ribose resulted less expressed in CV-AE group. Conclusions. This exploratory study showed different metabolomic profile of CML patients with CV-AE underwent TKI treatment, suggesting possible mechanisms of endothelial damage mediated by the accumulation of metabolites. Tyrosine, highly expressed in the CV-AE CML group, is a reliable marker of oxidative stress in various acute and chronic diseases.Metabolomics research has considerable potential for translating the metabolic fingerprint into personalized therapeutic strategies. These preliminary data should be confirmed in prospective clinical trials. Figure 1 Disclosures No relevant conflicts of interest to declare.

Download Full-text