Probability Of Event-free Survival Research Articles

Improving outcomes of hematopoietic stem cell transplant for leukemia in children and young adults in resource-limited setting

IntroductionAllogeneic hematopoietic stem cell transplantation (HSCT) is a curative approach in patients with relapsed and high-risk leukemia. This retrospective analysis aimed to investigate outcomes and risk factors associated with HSCT in children and young adults with hematological malignancies in a resource-limited setting. MethodsWe retrospectively evaluated 48 pediatric and young adult patients diagnosed with hematological malignancies who underwent HSCT at our institution between April 2017 and Jan 2023. ResultThe median age of the cohort was 10 years (6 months - 21 years), and the majority of patients underwent transplants for acute lymphoblastic leukemia (ALL) (n = 24; 50 %) and acute myeloid leukemia (n = 18; 37.5%). Median time to neutrophil and platelet engraftment were 15 days (range 9–28) and 18 days (range 9–40), respectively. One patient had primary graft failure. Cytomegalovirus reactivation occurred in 21 patients (43.8%). Seventeen patients received escalated donor lymphocyte infusion (DLI). With a median follow-up of 902 days (52–2490), the probability of event free survival and overall survival (OS) was 65.9% and 69.4%. OS for lymphoid and myeloid malignancies were 64.7% and 75.2%, respectively. Kaplan-Meier probabilities of OS for patients in first complete remission (CR), CR2, CR3, or with refractory disease were 80%, 76.2%, 0%, and 40%, respectively (p = 0.02). OS of the patients undergoing matched sibling donor (n = 17) or haploidentical HSCT (n = 31) was 70.6% and 69%, respectively (p = 0.989). ConclusionsOur study demonstrates excellent outcomes of patients with hematological malignancies undergoing allogeneic HSCT with similar outcomes in HLA-identical sibling donors and haploidentical first-degree family donors. Prophylactic DLI might be considered in patients with high-risk leukemia to prevent relapse, including ALL.

Correlation of urinary comprehensive genomic profile with risk of recurrence of BCG-unresponsive non-muscle invasive bladder cancer treated with atezolizumab in SWOG S1605.

529 Background: Radical cystectomy is recommended for patients with BCG-unresponsive (BU) non-muscle invasive bladder cancer (NMIBC) due to high risk of progression. Improved methods for assessing these risks would greatly facilitate the potential for bladder preservation. Here, we tested the capacity of the urinary comprehensive genomic profile (uCGP) to predict event-free survival (EFS) in patients with BU-NMIBC treated with atezolizumab in the single arm phase 2 trial SWOG S1605. Methods: Urine was collected from patients with BU NMIBC (CIS, Ta, T1) treated with at least one dose of intravenous atezolizumab at baseline and before the 5th cycle of therapy (3 months). The uCGP was assessed using UroAmp (Convergent Genomics). Risk scores for recurrence at baseline and at 3 months were calculated by a prespecified machine learning algorithm incorporating alterations in 60 genes and low pass whole genome sequencing, and categorized as high versus low. Molecular response was classified based on change in uCGP between the two time points. Risk scores and molecular response were submitted to SWOG for clinical correlation with EFS using a Cox model, adjusting for CIS status. Time to event was calculated from date of study entry (baseline risk) or from the 2nd collection time (3-month risk) to first high grade (HG) recurrence or persistent CIS at 3 months. Death unrelated to bladder cancer and patients last known to be alive without HG recurrence were censored at date of last visit. Results: Samples were provided at baseline in 89 patients and before the 5th cycle in 77; 68 had both samples available for paired analysis. The risk score at baseline was classified as high in 69% of samples (73% for CIS ±Ta/T1 and 62% for Ta/T1). At 12 and 18 months the EFS probabilities were 26% and 23% for high-risk and 67% and 51% for low-risk patients, respectively, with a HR of 2.82 (95% CI: 1.58, 5.03; p<0.001). The risk score at the 3-month timepoint was classified as high in 81% of samples, and the EFS probabilities at 12 and 18 months after urine collection were 26% and 22% for high-risk and 80% and 72% for low-risk patients, respectively, with a HR of 3.39 (95% CI: 1.41, 8.13; p<0.006). Molecular response to treatment was classified as complete (CR) in 8%, partial (PR) in 14%, stable (SD) in 25% and progression (PD) in 46%, with 7% having no detectable genomic abnormalities at both time points. Clinical recurrence was observed by 18 months in 0/6 patients with CR, 7/9 (78%) with PR, 11/14 (79%) with SD and 25/33 (76%) with PD by genomic profile. Conclusions: This study suggests that uCGP at baseline and after 4 cycles of treatment can identify genomic patterns associated with an increased risk of HG persistence, recurrence or progression in BU NMIBC treated with immune checkpoint inhibition. Future studies will determine if this can be used to guide early treatment intensification.

Relation between non-sustained ventricular tachycardia and major arrhythmic events in patients with dilated cardiomyopathy caused by titin truncating variants

Abstract Background Truncating titin variants (TTNtv) are the most frequent monogenetic cause of dilated cardiomyopathy (DCM). Current data suggest that nonsustained ventricular arrhythmia is common in patients with TTVtv but its relation to the risk of major arrhythmic events (MAE) is uncertain. Purpose To investigated the relationship between NSVT recorded on Holter ECG or implanted device and MAE in patients with DCM. Methods We retrospectively studied consecutively evaluated patients with DCM (left ventricle ejection fraction (LVEF) below 50%) on echocardiography and a pathogenic TTNtv. Patients with obstructive coronary artery disease, valvular disease, ventricular tachycardia ablation during follow-up time and follow-up less than one month were excluded. Survival was modelled from the initial Holter or device implantation. NSVT was defined as ≥3 consecutive ventricular beats at a rate >120 beats per minute, lasting for <30 s. MAE was defined as sustained ventricular tachycardia (VT), ventricular fibrillation (VF), sudden cardiac death, implantable cardioverter defibrillator (ICD) treated ventricular arrhythmias (appropriate shock and ATP). The clinical endpoint was MAE (sustained VT, VF, sudden cardiac death, ICD shocks and ATP) and multivariable analysis was performed using Cox proportional hazards models. Event-free survival probabilities were estimated using the Kaplan-Meier method, and comparisons of Kaplan-Meier curves were made using log-rank tests. Results The cohort comprised 58 men and 30 women [mean age 49 ± 15 years; mean follow-up 3.5 ± 1.8 years]. Symptoms were NYHA class I in 56 patients, class II in 25 patients, class III in 7 patients and class IV in none. Holter ECGs were performed in 77 patients, 41 of whom had NSVT. Twenty five patients had pacemaker/ICD in situ; 14 had NSVT. Six patients had MAE; 4 with NSVT. Univariate analysis association between MAE and LVEF ≤35% (hazard ratio (HR), 9.03; 95% confidence interval (CI), 1.49-54.71; P=0.017), prolonged (>8 beats) NSVT (HR, 6.71; 95% CI, 1.22-36.98; P=0.029) and fast (>200 bpm) NSVT (HR, 5.09; 95% CI, 1.02-25.47; P=0.048). Kaplan-Meier showed similar differences in freedom from MAE (LVEF ≤35%; P=0.004, long NSVT; P=0.025, fast NSVT; P=0.031). Conclusion Fast and prolonged NSVT is associated with a higher risk of MAE in patients with TTNtv.Characteristics at the beginningSurvival probability for freedom

The Effect of Package Time on Locally Advanced Oral Cavity Cancer Outcomes

Oral cavity cancer (OCC) with adverse pathologic features is treated with adjuvant radiation (RT) following definitive surgical resection. The 5-year overall survival (OS) in locally advanced OCC patients receiving adjuvant RT has remained stagnant at 60% for over 30 years. Although pathologic risk factors are well-established, the effect of clinical variables such as treatment package time (TPT) in the modern era of radiation and systemic agents is unclear. Examining a large, homogenous cohort of OCC patients, we hypothesized that TPT can predict OS and event free survival (EFS). A retrospective review of 359 adult patients with OCC treated with surgery and adjuvant RT with or without concurrent chemotherapy from 2012-2022 was performed at a single, high-volume center. Those without definitive surgery, treated to <50 Gy, or with a history of prior RT were excluded. TPT was defined as time from surgery to completion of RT. Other variables considered were sex, race, smoking status, AJCC 8 pathologic stage, perineural invasion (PNI), lymphovascular invasion (LVI), margin positivity, extranodal extension (ENE), and hospitalization between surgery and RT. Log rank tests were performed for OS and EFS where TPT was dichotomized into short (<97.5 days) and long (>97.5 days) groups based on the median TPT of the cohort. Univariate (UVA) and multivariate (MVA) cox regression analyses were performed for OS and EFS. A total of 234 patients met inclusion criteria. Median OS was 81.6 months. Median EFS was 50.0 months. Median OS was 51.1 months in the longer TPT group and was not reached in the shorter TPT group. Median EFS was greater with shorter TPT (72.6 vs 31.3 months). The longer TPT group had worse OS and EFS probabilities than the shorter TPT group (p = 0.006 and p = 0.059, respectively). On UVA, factors significantly associated with OS were TPT (p = 0.006), former/current smoker status (p = 0.003 and p = 0.011, respectively), pathologic stage IV (p<0.001), positive PNI (p<0.001) or LVI (p = 0.005), and ENE (p<0.001). On MVA for OS, shorter TPT (p = 0.026), former smoker status (p = 0.009), pathologic stage IV (p = 0.026), positive PNI (p = 0.009), and ENE (p = 0.05), remained significant. On UVA, factors significantly associated with EFS were former/current smoker status (p = 0.01/p = 0.04), pathologic stage IV (p<0.001), pT1/T2 (p = 0.018), positive PNI (p = 0.011) or ENE (p<0.001), and concurrent chemotherapy (p = 0.001). On MVA, former smoker status (p = 0.035) and positive PNI (p = 0.018) remained significant. Notably, of the 130 patients requiring hospitalization between surgery and radiation, 101 (78%) were prior/current smokers. In this large cohort of locally advanced OCC patients, TPT <97.5 days is associated with improved OS and EFS. Smoking history should be further explored for its potential contribution to treatment delay. Multidisciplinary coordination should be encouraged to minimize TPT.

Superior Graft-Versus-Leukemia Effect in Matched Unrelated Donor Versus HLA-Identical Sibling Pediatric Recipients Transplanted for Acute Lymphoblastic Leukemia within the Forum Study

Introduction: Allogeneic stem cell transplantation (HSCT) from either matched siblings (MSD) or matched unrelated donors (MUD) remains a standard option for children with high risk acute lymphoblastic leukemia (ALL), either in first complete remission (CR) or after relapse. The superiority of total body irradiation (TBI)/VP16 conditioning, compared to a chemotherapy based conditioning (fludarabine and thiotepa plus either busulfan or treosulfan) was demonstrated in theprospective, international, randomized non inferiority phase III study which enrolled 417 patients beyond the age of 4 years (y) transplanted for ALL in CR from either MSD or MD (Peters et al, JCO 2021; FORUM study). Besides the 201 patients randomized and actually receiving TBI from 2013 and 2018 in the randomizing countries, the FORUM trial included 411 additional children conditioned with TBI/VP16, enrolled either in countries where the randomization could not take place (for either legal or technical reasons) or in randomizing countries where TBI was chosen because the randomization was either skipped by physicians or families or had been discontinued. Methods: Here we report the 3-year consolidated results of these 612 patients ³4y and <21y treated in >100 pediatric centers in 26 countries following HSCT from either MSD (n=186, 30%) or MUD (defined as 9 or 10/10 4-digit molecular HLA-compatibility, n=426, 70%) after 12Gy TBI-VP16 for ALL in CR³1. Transplant details and statistical methods werepreviously reported in detail (Peters et al, JCO 2021). Of note, the main difference between the two groups was the GvHD prophylaxis consisting of cyclosporine A (CSA) +/- methotrexate (MTX) in MSD and serotherapy + CSA + MTX (Day 1, 3, 6, 11 post-HSCT) in MUD. Results: Patient's characteristics are reported in Table. Median age was 10y (4.0-20.8). The MSD and MUD groups were comparable, with the only exception of a larger use of peripheral blood and cord blood as stem cell source in the MUD population. In total, 299 pts were transplanted in CR1 (MSD, n=84; MUD, n=215) and 312 (MSD, n=102; MUD, n=210) in > CR1. In univariate analysis (figure), the Kaplan-Meier estimate of 3-year overall survival (OS) was significantly better in the MUD compared to the MSD group (83±2% vs 73±5%, respectively, P=0.041). Both the 3-year cumulative incidence (CI) of treatment-related mortality (TRM) and the 3-year probability of Event Free Survival (EFS) were comparable in the 2 groups analyzed (7±3% vs 7±1%, P=0.87 and 69±5% vs 83±2%, P=0.25, in MSD and MUD, respectively). The 3-year cumulative incidence of relapse (CIR) was higher in MSD (24±4% and 16±2%, respectively), although not statistically significant (p=0.08). The CI of acute GvHD was comparable in both groups, whereas the 3-year CI of cGvHD was higher in MSD than in MUD (19±3 vs 11±2%, P=0.07). The GvHD-relapse-secondary malignancy-free survival (GRFS) is significantly better in MUD than MSD (62±3 vs ±51±5%, P=0.04). In multivariate analysis, factors associated with superior OS include being transplanted from unrelated donor MUD, in CR1 and below the age of 14 years. Disease status at time of HSCT (i.e. CR1) was the only factor associated with better EFS and lower risk of post-transplant relapse. Conclusion: Our data indicate that the use of MUD is no longer a risk factor in HSCT for childhood ALL. The greater immune-genetic disparity in the matched unrelated donor/recipient pairs protects from the risk of disease recurrence, while the use of serotherapy prevents the occurrence of chronic GvHD, with both factors contributing to the observed improved GRFS in patients transplanted from an unrelated donor. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Inotuzumab Ozogamicin Induction Followed By Standard Chemotherapy Yields High Remission Rates and Promising Survival in Older (>55 Years) Patients with De Novo B-Lymphoblastic Leukemia (GMALL-Initial1 Trial)

Introduction: Acute lymphoblastic leukemia (ALL) represents approx. 5% of all newly diagnosed leukemias in patients (pts) between 55 and 70 years of age. Incorporation of novel antibody-based therapies in the first line induction therapy bears the potential of a significantly increased response rates and survival together with a reduction of treatment toxicity. Methods: This open label phase II study (ClinicalTrials.gov, identifier: NCT03460522) of the German Multicenter Study Group on Adult Acute Lymphoblastic Leukemia was conducted at 13 centers. Pts aged >55 years with newly diagnosed Ph/BCR-ABL negative B-precursor ALL (at least CD20 positivity of leukemic blasts) were eligible. The 1st induction cycle consisted of InO 0.8mg/m2 on day1 and 0.5mg/m2 on d8 and d15 together with dexamethasone 10 mg/m2 (day7-8, day14-17) and one intrathecal injection (i.th.) of methotrexate (MTX), cytarabine (AraC) and dexamethasone (Dex). The 2nd and 3rd induction cycle consisted of InO 0.5mg/m2 on day 1, 8 and 15 plus i.th. MTX/AraC/Dex. Pts achieving a complete remission (CR) were offered to receive 5 conventional consolidation therapies (3 x ID-MTX/asparaginase; 2 x ID-AraC) and one reinduction therapy (idarubicine/ AraC/ cyclophosphamide / Dex.) in combination with rituximab (for CD20+ ALL), followed by a maintenance therapy with 6-MP/MTX. The primary endpoint was event free survival (EFS) at 12-months follow-up. An event was defined as any of the following: persisting bone marrow blasts after 2 cycles of InO, relapse or death. An event rate of ≤40% at 12 months follow-up was considered to qualify the experimental treatment as very promising for additional testing. Results: 43 out of the 45 pts included were analyzed regarding the primary end point. Two pts were excluded per protocol from further analysis, as they received only one cycle of induction or withdraw consent. At diagnosis, median age was 64 years (range 56-80 years, 20 pts ≥65 years and 12 pts ≥70 years), median bone marrow blast count was 80% and median CD22 expression on leukemic blasts was 69% (range 21-99). 38 pts were diagnosed with a common- and 5 with a pro-B ALL. 42/43 pts completed all 3 cycles of induction therapy. All 43 pts achieved a complete remission (CR/CRi), mainly after the 1st induction. Median time between start of 1st induction to start 2nd induction, from 2nd to 3rd induction and from 3rd induction to 1st consolidation therapy was 21 days, 28 days and 30 days, respectively. Results of minimal residual disease (MRD), measured by real-time quantitative PCR, are available for all 43 pts, with 23/43 (53%) and 31/42 (74%) pts being MRD negative after 2nd and 3rd induction therapy, respectively. With a median follow-up of 697 days, the probability of OS at 1 and 2 years is 91% (95% C.I. 82-99%) and 81% (95% C.I. 69-94%), respectively. No patient died within the first 6 months after start of induction therapy. 5 events occurred within the first year after study inclusion, 3 deaths in CR and 2 relapsed ALL, resulting in event rate of 12% and a probability of EFS at 1 year (primary endpoint of the study) of 88% (95% CI 79-98). EFS at 2 years was 73% (95% CI 59-88). So far, 7 pts with persisting/reappearance of MRD (2 pts) or relapse (5 pts) were treated with blinatumomab. 9 pts received an aSCT (4 pts in CR1 and 5 pts >CR1), 6 of these pts are alive in CR. Regarding adverse events (AEs) during induction cycles 1, 2 and 3, most common AEs ≥CTC grade 3 reported were leukocytopenia (in 74%, 19% and 2% of all cases, respectively), anemia (37%, 5%, 0%), thrombocytopenia (49%, 7%, 2%) and elevation of liver enzymes (14%, 5%, 0%). One patient was reported with suspected veno occlusive disease (after 2nd induction therapy). Classical factors which may be associated with inferior survival outcomes like age, diagnosis of pro-B ALL, disease burden at diagnosis, co-morbidity or no MRD negative CR after induction had no significant impact on OS or EFS. Conclusion: Three cycles of InO as induction therapy for the treatment of older pts with de novo acute B-lymphoblastic leukemia resulted in a very high remission rate. Given that our study met the primary end point (predefined event rate at 1 year ≤40%, observed event rate 12%), these promising study results could be a rationale for integrating InO induction therapy in future treatment recommendations. Ideally, this novel induction therapy should be evaluated in prospective randomized trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clonal Myeloproliferative Disorders in Patients with Down Syndrome-Treatment and Outcome Results from an Institution in Argentina.

Simple SummaryAround 30% of children with Down Syndrome (DS) will develop Transient Abnormal Myelopoiesis (TAM) and 20% of them will progress to Acute Myeloid Leukemia (AML), mostly Megakaryoblastic Leukemia (AMKL). The optimal balance between treatment intensity and treatment-related toxicity has not yet been defined; neither the prognostic factors that determine the risk of developing AML nor the outcome. The aims of our retrospective study were to analyze the demographic/biological features of this population, identify possible risk factors and the optimal treatment. We observed that early intervention in TAM is effective to prevent a dismal outcome. The strongest poor-prognostic factor of DS-AML was sporadic DS-AML (non-AMKL immunophenotype), as well as complex karyotype and young age. Classical Myeloid Leukemia associated with DS (ML-DS) good outcome is mainly related to their low relapse rate. Even though the augmented sensitivity to chemotherapy seen in DS patients must be kept in mind, our data do not support the omission of high doses of cytarabine in ML-DS.Children with Down syndrome (DS) are at an increased risk of developing clonal myeloproliferative disorders. The balance between treatment intensity and treatment-related toxicity has not yet been defined. We analyzed this population to identify risk factors and optimal treatment. This single-center retrospective study included 78 DS patients <16 years-old with Transient Abnormal Myelopoiesis (TAM, n = 25), Acute Myeloblastic Leukemia (DS-AML, n = 41) of which 35 had classical Myeloid Leukemia associated with DS (ML-DS) with megakaryoblastic immunophenotype (AMKL) and 6 sporadic DS-AML (non-AMKL). Patients with DS-AML were treated according to four BFM-based protocols. Classical ML-DS vs. non-DS-AMKL were compared and the outcome of ML-DS was analyzed according to treatment intensity. Only four patients with TAM required cytoreduction with a 5-year Event-Free Survival probability (EFSp) of 74.4 (±9.1)%. DS-AML treatment-related deaths were due to infections, with a 5-year EFSp of 60.6 (±8.2)%. Megakaryoblastic immunophenotype was the strongest good-prognostic factor in univariate and multivariate analysis (p = 0.000). When compared ML-DS with non-DS-AMKL, a better outcome was associated with a lower relapse rate (p = 0.0002). Analysis of administered treatment was done on 32/33 ML-DS patients who achieved CR according to receiving or not high-dose ARA-C block (HDARA-C), and no difference in 5-year EFSp was observed (p = 0.172). TAM rarely required treatment and when severe manifestations occurred, early intervention was effective. DS-AML good outcome was associated with AMKL with a low relapse-rate. Even if treatment-related mortality is still high, our data do not support the omission of HDARA-C in ML-DS since we observed a trend to detect a higher relapse rate in the arm without HDARA-C.

Sex Differences In Presentation And Outcomes Of Cardiac Sarcoidosis

<h3>Background</h3> Sex differences exist in myocarditis, with male predominance. Sarcoidosis causes an inflammatory cardiomyopathy with proposed shared mechanisms to myocarditis. Sarcoidosis is typically female predominant, but most published cohorts of <i>cardiac</i> sarcoidosis (CS) are majority male. Sex differences in CS have not been reported. <h3>Methods</h3> A single center retrospective cohort of 254 CS patients was studied. Medical records were reviewed for CS presentation, treatment and outcomes. Sex differences were analyzed using two sample t-test, chi-squared test, or Fisher's exact test. <h3>Results</h3> : Of 254 patients with CS,149 (57%) were male and 109 (43%) were female. Males were more likely to present with ventricular tachycardia (VT) (26% vs 15%, p=0.04). Rates of reduced LVEF <50% (53% vs 45%, p=0.25) were similar, but females were more likely to present with clinical HF (47% vs 28%, p=0.002) at CS diagnosis. Initial PET scan demonstrated cardiac FDG uptake in 73% of males and 77% of females (p=0.22). Rates of steroid-sparing agent treatment were similar by sex, however females were more likely to receive an upfront (within 60 days of initiating treatment for CS) steroid-sparing agent (40% vs 29%, p=0.05). Among 114 patients with follow-up cardiac FDG-PET scans, there were no differences in improvement or worsening from initial scan based on sex. One year after CS diagnosis, 23% of males and 18% of females had reduced LVEF (p=0.86). Among patients who initially presented with reduced LVEF, rates of EF recovery (>50%) were similar among males and females (14% vs 14%, p=0.59). Males were more likely to have new or recurrent VT after CS treatment initiation (26% vs 12%, p=0.01), and to undergo VT ablation (17% vs 8%, p=0.056). Rates of LVAD and heart transplantation were similar. For the combined endpoint of new or recurrent VT, LVAD, OHT or death, the probability of event free survival was significantly lower for men (p=0.006). <h3>Conclusions</h3> : In this sample, males with CS were more likely to experience VT both at time of CS presentation and after treatment. Females were more likely to present with clinical HF. The cardiac phenotypes of CS may prompt further evaluation for CS with these sex differences in mind. These findings call for further investigations into patient-related and mechanistic differences based on sex in CS.

Adjuvant tamoxifen switched to exemestane treatment in postmenopausal women with estrogen receptor-positive early breast cancer: A pragmatic, multicenter, and prospective clinical trial in China.

This post-approval safety study assessed the efficacy and safety of exemestane after 2-3 years of tamoxifen treatment among postmenopausal women with estrogen receptor-positive (ER+) early breast cancer in China. Enrolled patients had received 2-3 years of tamoxifen and were then switched to exemestane for completion of 5 consecutive years of adjuvant endocrine therapy. The primary endpoint was the time from enrollment to the first occurrence of locoregional/distant recurrence of the primary breast cancer, appearance of a second primary or contralateral breast cancer, or death due to any cause. Other endpoints included the proportion of patients experiencing each event, incidence rate per annum, relationships between human epidermal growth factor receptor 2 status and time to event, and relationship between disease history variables and time to event. Overall, 558 patients were included in the full analysis set: 397 (71.1%) completed the study, 20 experienced an event, and 141 discontinued [47 owing to an adverse event (AE); 37 no longer willing to participate]. Median duration of treatment was 29.5 (range, 0.1-57.7) months. Median time to event was not reached. Event-free survival probability at 36 months was 91.4% (95% CI, 87.7%-95.1%). The event incidence over the total exposure time of exemestane therapy was 3.5 events/100 person-years (20/565). Multivariate analysis showed an association between tumor, lymph node, and metastasis stage at initial diagnosis and time to event [hazard ratio: 1.532 (95% CI, 1.129-2.080); P=0.006]. Most AEs were grade 1 or 2 in severity, with arthralgia (7.7%) being the most common treatment-related AE. This study supports the efficacy and safety of exemestane in postmenopausal Chinese women with ER+ breast cancer previously treated with adjuvant tamoxifen for 2-3 years. No new safety signals were identified in the Chinese population.

Outcome of BCR-ABL/Philadelphia Positive Acute Lymphoblastic Leukemia: A Single Centre Experience from Developing Country

Introduction : Philadelphia (Ph) positive Acute Lymphoblastic Leukemia (ALL) is an aggressive type of leukemia and is uniformly associated with an unfavorable outcome when treated with standard chemotherapy. Current treatment of Ph positive ALL comprises of standard systemic and CNS directed chemotherapy along with tyrosine kinase inhibitor (TKIs) to achieve molecular response followed by Allogeneic stem cell transplantation (Allo-SCT). We aim to present the clinical profile and outcomes of Ph + ALL patients treated at our centre.Material and Methods : This is a retrospective study where medical records of 248 patients who were diagnosed and treated for ALL from 1-Jan-2011 to 30-Jun-2016 at our centre were analyzed. Out of those 248 patients, 51 patients (20.5%) were Ph chromosome or BCR-ABL positive and were eligible for the study. Medical records were reviewed and information regarding patient profile, disease characteristics and treatment were collected. Probabilities of Event Free Survival (EFS) was calculated using the Kaplan Meier estimate; the log rank test was used for univariate comparison. A p-value <0.05 was considered to be significant. All statistical analyses were performed using Statistical Package for Social Sciences (SPSS 20, IBM SPSS Statistics for Windows, version 20.0; IBM Corp., Armonk, NY, USA).Results : Out of 51 Ph positive ALL patients, 44 patients were started on treatment and were included in this study. Twenty five (57%) were males; median age of the patients was 35yrs (14-76yrs). Median WBC count was52.3 x 103/mm3 (0.7-432.4 x 103/mm3), 5 patients were CNS 3 while rest were CNS 1. Cytogenetic information was available for 35 patients, out of whom 28 patients had Ph chromosome with 16 patients having additional cytogenetic abnormality. All patients were BCR-ABL positive. Induction chemotherapy was given in all 44 patients. Post induction 40 patients achieved complete remission (CR) while one patient achieved CR after salvage chemotherapy, 2 patients were induction failure and 1 patient died during induction due to fungal pneumonia. Molecular responses were assessed in 26 patients, 11 (42%) achieved major molecular remission (MMR). Thirty eight patients went on to receive consolidation therapy with chemotherapy with TKI (n=24) or chemotherapy with TKI followed by Allo-SCT (n=14).For allo-SCT (matched sibling donor n=10 with Myeloablative conditioning n=8 and reduced intensity conditioning (RIC) n=2, haplo-identical donor transplant n=4 with non-myeloablative conditioning n=3 and RIC n=1),commonly used regimes were TBI based in 9/14 patients. Six patients experienced acute GvHD of grade II-IV and 7 patients developed chronic GvHD (extensive chronic GvHD in 1 patient). One patient died in the peri-transplant period (D+14) due to klebsiella sepsis. A total of 10 episodes of CMV reactivations were seen. Among other infections seen in post transplant patients were 1 patient each with pulmonary tuberculosis, esophageal tuberculosis, fungal pneumonia and herpes-zoster. Mortality 6/14 including one relapse mortality and 5 TRM with EFS of 57% at median follow up of 16 months (3-49 mo).Out of 24 patients on chemotherapy with TKI, 8 patients are in complete remission, while 5 patients defaulted, 11 patients relapsed with subsequent salvage therapy and Allo-SCT in 6 patients but ultimately death in all 11 patients with EFS of 42% (8/19, after excluding defaulted patients) at median follow up of 12 months (1-45 mo).On comparing patients that underwent Allo-SCT versus those that received only chemotherapy, it was found that the two groups were comparable except for age (Table - 1). Median age was higher in the chemotherapy alone group. No statistically significant difference in EFS was found in patients who underwent Allo-SCT vs chemotherapy alone (57% vs 42%, p= 0.845). (Figure 1)Conclusion : Allo-SCT can improve the survival of Ph positive ALL patients. There is a need to conduct a prospective randomized study with large number of patients to clearly define the beneficial role of Allo-SCT in this era of universal TKI usage. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Ponatinib and Chemotherapy in Young Adults with De Novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Results of Ponalfil Clinical Trial after Completion of Recruitment

Background and objective. The combination of tyrosine kinase inhibitors (TKI) and chemotherapy (intensive, attenuated or minimal) has improved the prognosis of patients (pts) with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). The combination of HyperCVAD and ponatinib has improved the molecular response and survival compared with other combinations of chemotherapy with first or second generation TKI (Jabbour E, et al, Lancet Haematol. 2018; 5:e618-e627). The Spanish PETHEMA group conducted the phase 2 PONALFIL trial, which incorporates ponatinib to the same induction and consolidation schedule of the ALL Ph08 trial (Ribera JM et al. Cancer 2019;125:2810-2817) The results of this trial after completed recruitment are herein reported. Patients and method. The PONALFIL trial (NCT02776605) combined ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin and prednisone) followed by consolidation (high-dose methotrexate, ARA-C, mercaptopurine, etoposide) and allogeneic HSCT. TKI use as maintenance was only scheduled for pts with persistence or reappearance of MRD. By July 2020 the 30 scheduled pts were recruited. The response to therapy (complete morphological [CR], molecular [complete, CMR or major, MMR] after induction and before allogeneic HSCT) (assessed by centralized BCR-ABL/ABL ratio),event-free survival (EFS), overall survival [OS]) and toxicity are herein analyzed. Results. Median age was 50 (20-59) years and 14/30 pts were female. One pt showed CNS involvement at diagnosis. ECOG score at diagnosis was &amp;lt;2 in 86% of pts. Median of WBC count was 6.4 (0.6-359.3) x109/L, Hb 90 (63-145) g/L, platelets 38 (11-206) x109/L. The immunologic phenotype was common in 26 cases, with molecular isoform p190 in 20 patients (67%), p210 in 9 (30%) and p230 in 1 (3%). CR was attained 26/26 patients (100%) (4 are still on induction therapy), with CMR in 11/26 cases (42%), MMR in 6/26 (23%) and no molecular response in 9/26 (35%)).Two patients withdrew the trial (thrombosis of the central retina artery and severe intestinal infection, one case each). Consolidation was given to 24 patients, 2/24 are receiving consolidation and 22 patients received allogeneic HSCT (14 in CMR, 6 in MMR, 2 without molecular response). No relapses before HSCT were detected. No transplant-related mortality was observed to date, but 1 patient withdrew the trial by severe GVHD. Ponatinib was given after HSCT in 4 pts due to loss of molecular response. Three pts relapsed after HSCT, one of them after documented loss of molecular response. All pts are alive (median follow-up of 4.5 months, range 0.5-26.2.2). The EFS probability at 30 months was 91% (79%, 100%) (Figure 1). One hundred and two adverse events (AE) have been registered in 20 patients, 25 of whom were severe (SAE) and occurred in 14 patients, prompting to withdrawn of the trial in 3 (thrombosis of the central artery of the retina, severe bowel infection, grade IV aGVHD, one case each). The most frequent AE were hematologic (26%), gastrointestinal (15%), infections (10%), hepatic (8%) and cutaneous (5%). Cardiovascular events occurred in 2 patients (angor pectoris and thrombosis of central artery of the retina, one case each). Conclusions. The preliminary results of the PONALFIL trial after recruitment completed show a high short-term antileukemic efficacy with acceptable toxicity profile. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. Event free survival (EFS) of the whole series. Figure 1 Disclosures Ribera: Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau; Pfizer, Amgen: Research Funding. Martinez-Lopez:Incyte: Consultancy, Research Funding; Novartis: Consultancy; BMS: Consultancy, Research Funding; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria. Garcia-Sanz:Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Gilead: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Pharmacyclics: Honoraria; Takeda: Consultancy, Research Funding.

No benefit of Interfant protocols compared to BFM‐based protocols for infants with acute lymphoblastic leukemia. Results from an institution in Argentina

Infant acute lymphoblastic leukemia (ALL) is an infrequent disease characterized by clinical and biological features related to poor prognosis. Adapted therapies were designed without a clear consensus regarding the best treatment options. We aimed to compare the outcome between infant ALL cases receiving Interfant versus BFM-based protocols. This is a retrospective observational study. From April 1990 to June 2018, infant ALL cases were enrolled in one of the five consecutive treatment protocols. Clinical, demographic, and biological features and outcome were evaluated. A comparative analysis was performed between Interfant protocols and BFM-based protocols. During the studied period, 1913 ALL patients were admitted and 116 (6%) were infants. Treatment administered was: ALL-BFM'90 (n=16), 1-ALL96-BFM/HPG (n=7), Interfant-99 (n=39), Interfant-06 (n=35), and ALLIC-BFM'2009 (n=19). The 5-year event-free survival probability (EFSp) was 31.9(standard error [SE] 4.6)% for the entire population, with a significant difference among risk groups according to Interfant-06 criteria (P=.0029). KMT2A-rearrangement status was the strongest prognostic factor (P=.048), independently of the protocol strategy. The median time for relapse was 24.1months for patients with minimal residual disease (MRD)-negative versus 11.5months for those with MRD-positive (P=.0386). EFSp and cumulative relapse risk probability (CRRp) were similar. Interfant protocols showed comparable induction (8.1% vs 7.1%, P=.852) and complete remission mortality (21.6% vs 28.6%, P=.438), failing to reduce the relapse rate (48.5% vs 30.7%, P=.149). Interfant protocols and BFM-based protocols presented comparable results. The risk group stratification proposed by Interfant-06 was validated by our results, and MRD seems useful to identify patients with an increased risk of early relapse.

The neutrophil/lymphocyte ratio ≥3.5 is a prognostic marker in diffuse large B-cell lymphoma: a retrospective analysis from the database of the Italian regional network ‘Rete Ematologica del Lazio per i Linfomi’ (RELLI)

In solid tumors and lymphomas, the neutrophil/lymphocyte (N/L) ratio at diagnosis has been shown to be a prognostic factor. The aim of our study was to validate the originally reported N/L ratio cut-point of 3.5 in patients with diffuse large B-cell lymphoma (DLBCL) registered in an Italian real-life database. The prognostic role of the N/L ratio at diagnosis on event-free survival (EFS) and overall survival (OS) was assessed in 505 patients with DLBCL. Patients with an N/L ratio <3.5 (n = 249) had a 4-year EFS probability of 76% and OS probability of 86%, significantly higher than the 4 year EFS rate of 48% and OS rate of 64% in patients with N/L ratio ≥3.5 (n = 256, both p<.0001). The N/L ratio was an independent prognostic factor in the multivariate analysis including the IPI score, and could separate patients with a low/intermediate risk IPI (IPI <3).

Clinical and biological features of acute myeloid leukemia with MLL gene rearrangements in children and results of therapy according to protocols AML-MM-2000/2006 in the Republic of Belarus

Objective of the study . Analysis of the treatment outcomes of patients with MLL rearrangements in the Republic of Belarus within protocols AML-MM-2000 and AML-MM-2006.Materials and methods . The study included 151 patients with newly diagnosed acute myeloid leukemia (AML) who were treated according to protocol AML-MM-2000 and AML-MM-2006. 11q23 abnormalities were detected in 40 (26.5 %) out of 151 patients.Results . The performed analysis of the survival outcomes of patients with 11q23 depending on the protocol showed that the probability of 5-year event-free survival (EFS) was significantly better (p = 0.0110) in children receiving treatment under protocol AML-MM-2006 (86 ± 13 %) compared with that of the patients included in protocol AML-MM-2000 (23 ± 12 %). Using protocol AML-MM-2006 allowed reducing the cumulative incidence of relapse (CIR) in this cohort from 46.2 ± 15.1 to 14.3 ± 14.3 % (p = 0.1609). EFS probability in recipients of allogeneic hematopoietic stem cell transplantation (alloHSCT) was 100 %, whereas in the group without alloHSCT – 31 ± 12 %, p = 0.0359. The treatment outcomes of patients with t(1;11) are comparable to those with CBF leukemia. The risk of relapse in patients with t(10;11) is higher than in the rest of the 11q23 cohort (62.5 ± 19.2 % versus 21.9 ± 7.5 %; p = 0.0136). CIR in patients with t(9;11) decreased from 42.8 % in protocol AML-MM-2000 to 15.4 % in protocol AML-MM-2006 (p = 0.1411).Conclusion . For the described cohort of patients alloHSCT is the best option for post-remission therapy. The worst prognosis is determined in patients with t(10;11), whereas the presence of t(1;11) is a favorable prognostic factor. Using the arm with cladribine showed to be effective in patients with t(9;11). To obtain reliable outcomes, we consider it reasonable to continue the study with the use of cladribine in patients with t(9;11).

Genotypes of SLC22A4 and SLC22A5 regulatory loci are predictive of the response of chronic myeloid leukemia patients to imatinib treatment

BackgroundThrough high-throughput next-generation sequencing of promoters of solute carrier and ATP-binding cassette genes, which encode drug transporters, we aimed to identify SNPs associated with the response to imatinib administered for first-line treatment of patients with chronic myeloid leukemia.MethodsIn silico analysis using publicly available databases was done to select the SLC and ABC genes and their promoters for the next-generation sequencing. SNPs associated with the imatinib response were identified using Fisher’s exact probability tests and subjected to the linkage disequilibrium analyses with regulatory loci of concerned genes. We analyzed cumulative achievement of major molecular response and probability of event free survival in relation to identified SNP genotypes in 129 CML patients and performed multivariate analysis for determination of genotypes as independent predictors of outcome. Gene expression analysis of eight cell lines naturally carrying different genotypes was performed to outline an impact of genotypes on the gene expression.ResultsWe observed significant differences in the frequencies of the rs460089-GC and rs460089-GG (SLC22A4) genotypes among rs2631365-TC (SLC22A5) genotype carriers that were associated with optimal and non-optimal responses, respectively. Loci rs460089 and rs2631365 were in highly significant linkage disequilibrium with 12 regulatory loci in introns of SLC22A4 and SLC22A5 encoding imatinib transporters. Genotype association analysis with the response to imatinib indicated that rs460089-GC carriers had a significantly higher probability of achieving a stable major molecular response (BCR-ABL1 transcript level below or equal to 0.1% in the international scale). In contrast, the rs460089-GG represented a risk factor for imatinib failure, which was significantly higher in rs460089-GG_rs2631365-TC carriers.ConclusionsThis exploratory study depicted potentially important genetic markers predicting outcome of imatinib treatment, which may be helpful for tailoring therapy in clinical practice.

Efficacy and prognostic risk factors of childhood relapsed acute lymphoblastic leukemia: analysis from a single center

Objective To investigate the efficacy and prognostic risk factors of ALL-R-2003 protocol in the treatment of relapsed childhood relapsed acute lymphoblastic leukemia (ALL) in single center. Methods A retrospective study of clinical data of 51 children with relapsed ALL from January 2004 to December 2014 was performed by using SPSS version 19.0 statistical software for statistical analysis. Results The median age at initial diagnosis of 51 patients was 5.5 years (range, 0.8-13.4 years). The median time from initial diagnosis to relapse was 25 months (range, 3-68 months) and follow-up time was 39 months (range, 3-116 months). The relapse rate in the standard-risk, intermediate-risk and the high-risk groups were 27.5% (14/51), 29.4% (15/51) and 43.1% (22/51), respectively. The probability of 3-year overall survival (pOS) after relapse was (18.8±5.9)% and the probability of event free survival (pEFS) was (16.2±5.8)%. The 3-year pOS in very early relapse, early relapse and late relapse were 0, (11.7±7.7)% and (51.7±14.8)%, respectively (P= 0.000). There was no statistical difference in survival rate of different immunophenotype groups and sites of relapse (P> 0.05). The 3-year pOS of group S1, S2, S3, S4 were (50.0±35.4)%, (39.9±1.3)%, (10.0±9.5)% and 0, respectively (P= 0.000). The 3-year pOS of bcr-abl and MLL gene positive groups were (25.0±21.7)% and 0, respectively, with no statistically significance compared with the negtive group [(24.1±12.0)%] (P> 0.05). The 3-year pOS rates of children with bone marrow transplantation and without transplantation were (40.0±15.5)% and (13.0±5.9)% respectively (P= 0.038). Conclusions The children who in high risk group at initial diagnose are easily to meet earlier relapse and poorer prognosis. The survival period after relapse of bcr-abl or MLL gene positive cases is very short. Bone marrow transplantation can improve survival rate. Risk group at initial diagnose, relapse time and transplantation are the main factors influencing prognosis, and the relapse time and transplantation are the independent prognostic factors for relapsed childhood ALL. Key words: Leukemia, lymphocytic, acute; Relapse; Risk factors; Prognosis; Child

A review of the literature on childhood Burkitt lymphoma in Nigeria

Background: Burkitt Lymphoma is common childhood tumour in sub Saharan Africa but the lack of centralized database on childhood cancer in Nigeria has made it difficult having a nationwide picture of its occurrence in the country.Objectives: This study was aimed at pooling published data from across the country with the hope of providing an overview of the profile of the disease in Nigeria.Methods: literature search was carried out on Pub Med/MEDLINE and Cochrane databases for all articles published between January 1975 and July 2015 using search strings such as children, cancer, Burkitt’s, epidemiology, prevalence, treatment and Nigeria. Based on specific criteria, 39 studies were included.Results: Burkitt Lymphoma was the most common childhood malignancy in most parts of the country accounting for 18.3- 65.0% of malignant tumours but a few centers observed Retinoblas-toma as the most common. There was a decline in the frequency of Burkitt lymphoma in Ibadan from 1960-2010 and in Lagos. Peak ages of occurrence ranged from 5- 10 years, more males and children from low socio-economic classes were affected. Different centers reported predominant involvement of either the jaw or the abdomen but there were slightly more centers with predominance of the jaw. Retrospective studies yielded an estimated survival of 15-23% while the Event Free Survival probabilities at two years was 43% and 48% for the Nigerian centers that participated in an international study.Conclusion: Burkitt Lymphoma is a common tumour in Nigeria. Establishment of Cancer registries for better data capture and funding for better treatment outcomes is recommended.Keywords: Burkitt Lymphoma; Nigeria; childhood; tumours; cancer

Analysis of the Impact of Donor-Recipient ABO Mismatch on Outcomes of HLA-Haploidentical (HI) Hematopoietic Stem Cell Transplantation (HSCT)

Background:It is estimated that 30-50% of allogeneic hematopoietic stem cell transplants (HSCT) have some type of ABO incompatibility. There are inconsistencies in the literature regarding the impact of recipient/donor ABO mismatch (MM) on HSCT outcomes including overall (OS), event-free survival (EFS), relapse, and acute and chronic graft-versus-host disease (GVHD) in conventional myeloablative or reduced intensity settings. This may be a consequence of heterogeneity in treatment approaches and patient populations studied. In addition, little is known about the effect of ABO MM on outcomes after HI HSCT. To address these issues, we analyzed the effects of various recipient/donor ABO combinations on post HI HSCT outcomes in a population of patients treated on the uniformly designed Jefferson 2-step HSCT method. In this approach, after conditioning, patients received fixed dose of T cells (step 1), followed 2-3 days later by cyclophosphamide (CY) for bidirectional tolerization. Two days after CY, patients received the CD 34-selected donor product (step 2). Our goal was to elucidate the impact of various ABO recipient/donor combinations on outcomes in a homogeneous HI HSCT setting.Methods:This is a preliminary, retrospective evaluation of 167 patients with hematologic malignancies undergoing a 2 step HI HSCT between 2006 and 2015. Patients were divided into 3 ABO groups: major MM (MM in recipient to graft direction), minor MM (MM in graft to recipient direction) and matched. The groups were analyzed for the primary statistical end point, the association of ABO incompatible HI HSCT with EFS (death from disease progression or relapse). Secondary end points were the association of ABO incompatibility with OS, non-relapse mortality (NRM) and acute and chronic GVHD. The probabilities of EFS and OS were estimated by Kaplan-Meier (KM) method with log-rank analysis. Multivariate analysis to assess impact of ABO group on EFS and OS controlling for confounding variables (age, disease status at HSCT, conditioning intensity, interval from diagnosis to HSCT) was performed using Cox proportional hazards. Cumulative incidence functions with competing risk analyses were used to estimate probabilities of relapse, NRM, acute and chronic GVHD.Results: The median age and follow-up of the study group was 55 years and 33.8 months (range: 0.83-97.67 months) respectively. A total of 103 (61.7%) donor-recipient pairs were ABO identical, 28 (16.8%) major MM, and 36 (21.5%) minor MM. KM analysis showed that patients with minor MM had higher EFS but lower OS as compared with matched or major MM groups. This was recapitulated on multivariate Cox analysis, where EFS (HR=0.70, CI 0.30-1.66, p=0.43) was higher, but OS (HR=1.13, CI 0.65-1.97, p= 0.65) was lower in patients with minor MM. On competing risk analysis, NRM was higher (HR=1.67, CI 0.83-3.38, p=0.15) while relapse was lower (HR=0.59, CI 0.27-1.30, p=0.19) in minor MM group. The risk of grades 2 to 4 acute GVHD was significantly lower in patients with minor MM (HR=0.29, CI 0.10-0.88, p=0.02). Risks of acute GVHD grades 3 to 4 and chronic GVHD were not significantly different for any group, possibly due to few events in these categories.Discussion:To the best of our knowledge, this is the first assessment of the impact of ABO incompatibility on outcomes after HI HSCT. The strength of this study is the uniformity of treatment protocol and testing group. The analysis suggests that ABO minor MM has different effects on outcomes than major MM or matched groups which were surprisingly similar to each other. These findings were highlighted by the association of minor MM with decreased incidence of acute GVHD, the only finding that reached statistical significance. That minor MM was associated with less relapse and greater EFS may be indicative of a decreased need for immunosuppression in the group, but this relationship does not explain the lower OS and higher NRM in this group. The weakness of the analysis is the small sample size, especially in some subgroups. While most findings failed to reach statistical significance, the analysis was uniform in that minor ABO MM was different from other categories, possibly due to less alloreactivity in this group, thus impacting rates of acute GVHD and survival. These findings support the need for prospective research in this area with larger groups of patients.Non-relapse MortalityAcute GVHD 2-4 [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Leukocyte Count Defines Patients on Risk for Thrombotic Complications with Well Controlled Essential Thrombocythemia- Data from a Patient- Registry

There is compelling evidence that white blood cell (WBC) counts impact the risk of thrombosis in patients with myeloproliferative neoplasms (MPN) (Barbui Blood 2013). Moreover, recent publications disclosed significant differences regarding certain disease characteristics and the course of disease in WHO 2008 (Tefferi Blood 2007) classified essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (PMF) (Kvasnicka Am J Hematol 2008; Barbui JCO 2011; Buxhofer-Ausch Am J Hematol 2012). Hence, patients cohorts classified prior to WHO 2008 may likely consist of a mix of patients with ET and prefibrotic PMF.We aimed to reproduce the influence of WBC counts on the thrombotic risk in patients under real-life conditions. Therefore we assessed data of 825 Austrian patients from a patient registry for anagrelide in ET that was initiated 2001 in Austria due to an official authorities demand and is now being maintained in several Central European countries.Efficacy of treatment was assessed by investigating the course of platelet counts and event free survival relating to the first minor or major thrombotic event. WBC counts from the first available time points were correlated with the first thrombotic event. The cut off for the WBC subgroup analysis was set at 8,5 G/l. Statistical analysis was performed using the open-source R statistical software package, version 3.0.2. Non-parametric two-sided 95% confidence intervals for medians were calculated. Survival probabilities were assessed by applying the Kaplan-Meier method. For the comparison of time to event between the leukocyte- specific subgroups the log-rank test was used.Median Follow up of the study cohort is 3,07 years. Platelet count at start of anagrelide was median 777 G/l (95% CI 757-803). After 12, 24 and 36 months patients presented with median platelet counts of 473, 457 and 438 G/l, respectively. Median WBC count at start of therapy was 9 G/l (95% CI 8,7-9,3) and after 12, 24 and 36 months 8,5 G/l, 9,2 G/l and 8,7G/l, respectively. Incidence of thrombotic events per 100 patient- years was 5,14 for all events and 1,65 for major events only. 102 patients experienced at least one minor or major thrombotic event (major events n=36). Median time to the first minor or major thrombotic event was 1,27 years. Probability of event free survival at 1 year is 94,4% and at 3 years 87,6%. Patients with a baseline WBC count of higher than 8,5 G/l exhibit a significantly shorter probability of event free survival than patients below the cut off (p= 0,007 for all thrombotic events; p= 0,026 for major events only).This data proof the efficacy of anagrelide in lowering platelet counts and reducing significantly the risk of thrombotic events in patients with ET. The significantly shorter event free survival of patients with a WBC count above 8,5 G/l confirms earlier studies for the first time in a real-life setting. This result emphasizes the separation of true ET from prefibrotic PMF by using the WHO 2008 classification. Moreover, further investigations are needed to assess, whether a correlation of certain platelet and leukocyte counts modifies the risk of thrombotic events in MPN. DisclosuresSchloegl:AOP Orphan Pharmaceuticals AG: Research Funding.

Absolute Lymphocyte Counts at the End of Induction Is a Prognostic Indicator in Childhood Acute Lymphoblastic Leukemia

BACKGROUND: Recently, several studies have demonstrated that absolute lymphocyte counts (ALC) after induction therapy predicted treatment outcome. To address this issue, we here assessed the impact of the ALC at the end of induction therapy on outcomes in childhood ALL.METHODS: We reviewed 141 cases of pediatric ALL with 1-21 years of age treated on the Japan Association Childhood Leukemia Study group ALL-02 series of treatment trials between 2002 and 2013. Patients with Philadelphia chromosome-positive ALL were excluded. Variables retrospectively analyzed included ALC at several time points during remission induction, age at diagnosis, gender, initial white blood cell count (WBC), cytogenetics, immunological phenotype, stratified risk, treatment response for bone marrow (the percentage of blasts at day 15), and outcome. Events in the analysis of event-free survival (EFS) included induction failure, death, relapse and secondary malignant neoplasm. The comparison of categorical variables between groups was performed by chi-square test. The probability of EFS and overall survival (OS) were analyzed with the use of the Kaplan–Meier method and a stratified log-rank test. A multivariate analysis of survival was performed with the use of a Cox proportional-hazard model to evaluate the treatment effect with adjustment for stratification factors.RESULTS: The subjects included 121 of B-precursor ALL, 10 of T cell ALL, and 4 of acute mixed lineage leukemia/ acute unclassified leukemia. We found high WBC count at diagnosis (>100K/microL) and slow early responder for bone marrow at day 15 to be an unfavorable prognostic indicator, and also the ALC at the end of induction (day29) to be a statistically significant predictor of improved OS and EFS in our cohort. Patients with ALC ≥ 800/microL had a superior 5-year overall survival (100 ± 1.7% vs 88.1 ± 4.3 %, p=0.0001) and EFS (98.3 ± 1.7% vs 81.8 ± 5.0 %, p=0.0001). Multivariate analysis demonstrated that ALC at day29 was an independent, clinically significant predictor of improved EFS and OS after controlling WBC at diagnosis, gender, age at diagnosis, and cytogenetics. Multiple regression analysis adjusting for initial WBC count, peripheral blast counts at day8, and cytogenetics, also revealed an independent relationship (p=0.005) between treatment response (the percentage of blasts at day 15) and ALC at day29.CONCLUSIONS: ALC is a simple, statistically significant prognostic factor in childhood ALL that may refine current risk stratification algorithms. DisclosuresNo relevant conflicts of interest to declare.