Acute Lymphoblastic Leukaemia Has a Poor Outcome in Children with Down Syndrome Due to Infective Death in Remission (Results of UK MRC ALL 97 Trial).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 873-873 ◽  
Author(s):  
Josu de la Fuente ◽  
Sue Richards ◽  
David K. Webb ◽  
Ian M. Hann ◽  
Christopher D. Mitchell ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
High Rate ◽  
Childhood All ◽  
Free Survival ◽  
Children With Down Syndrome ◽  
Medical Research Council Trial ◽  
The Uk

Abstract Acute lymphoblastic leukaemia (ALL) has a poorer outcome in children with Down syndrome (DS) which has been attributed in the past to a higher incidence of infective death in remission and late relapses. We report on the outcome of children with DS enrolled on the UK Medical Research Council trial for childhood ALL, MRC ALL 97, between January 1997 and June 2002. Thirty seven children had DS (2%), of whom three were treated on the high risk protocol (HR1). Thirty-three (89%) achieved complete remission at the end of induction, 3 died during induction (8%), and one died later without remission. The median follow up was 4.9 years (2.4–7.8). The 5-year event free survival (EFS: 48.0%, SD 8.9) was not an improvement on the previous MRC UKALL XI trial (57.9%, SD 8.0, p=0.2) and was significantly worse than for children without DS (p<0.00005). At the time of follow up, 46% of the children had died (n=17). Five patients suffered relapse, and the relapse rate was not significantly different from those without DS. One patient known to have cardiac disease died during maintenance due to arrhythmia and 8 died of infection, resulting in a significantly higher rate of death in remission (28%) than in children without DS (3%, p<0.00005). Infective deaths were associated with intensification therapy, except in one child who died during interim maintenance. It was possible to isolate a microorganism in 50% of the cases (two cases of Pseudomonas, one Staphylococcus aureus, one Staphylococcus epidermidis and yeast) plus Rhinovirus was found in a nasopharyngeal aspirate of a fifth case with clinical evidence of bacterial sepsis. For the randomised comparisons (prednisolone versus dexamethasone n=30, mercaptopurine versus thioguanine n=23), results within the DS patients were not significantly different from those in all patients, with benefit for dexamethasone. The increase in remission deaths with DS was greater with prednisolone, and with mercaptopurine (p for interaction = 0.0002, <0.00005, respectively). The revision of the trial in 1999 which adopted the template of CCG 1952 which improved EFS, did so for DS patients also, with no change in the DS remission death rate. In conclusion, children with DS may benefit from increased treatment intensity but still have an unacceptably high rate of infective death in remission.

scholarly journals Preliminary Outcomes of Children and Young Adults with Acute Lymphoblastic Leukaemia and Down Syndrome (DS-ALL) on UKALL 2011. Reduction in Treatment-Related Mortality with De-Escalated Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 656-656
Author(s):  
Sara Ghorashian ◽  
Sujith Samarasinghe ◽  
Amy A Kirkwood ◽  
Rachael Hough ◽  
Clare Rowntree ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Acute Lymphoblastic Leukaemia ◽  
Research Funding ◽  
Advisory Board ◽  
Drug Induction ◽  
Risk Patients ◽  
The Uk ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Introduction Reported outcomes for children with Downs syndrome (DS) and acute lymphoblastic leukaemia (ALL) treated on our previous national study, UKALL 2003, were inferior compared to non-DS children. 5 year event free survival (EFS) for DS children was 65.6% vs. 87.7% for non-DS children and 5 year overall survival (OS) was 70.0% vs. 92.2% (British Journal of Haematology 2014; 165: 552-555). Excess treatment related mortality (TRM, 21.6% vs. 3.3% at 5 years) in children with DS-ALL was primarily due to infection. Similar results have been reported by other study groups. In our successor study, UKALL 2011, we employed several steps of de-escalation for DS-ALL patients compared to standard therapy. Here, we report that de-escalated therapy has resulted in a dramatic reduction in TRM for children with DS-ALL treated in the UK. Methods DS-ALL patients treated on UKALL 2011 had their treatment modified in the following respects: 1)NCI high risk patients did not receive anthracycline in induction unless they had a slow early response at day 15; 2) two years maintenance was given for both boys and girls; 3) no pulses were given in maintenance for MRD low risk patients. In addition, we recommended use of prophylactic antibiotics during induction and intensive phases of treatment. Fisher's exact test was used to compare induction mortality in the DS and non-DS pts. OS was defined as time from registration to death. EFS was defined as time from registration to first event (induction failure, relapse, second malignancy or death from any cause). The Kaplan-Meier method was used for survival estimation. Results The UKALL 2011 trial opened to recruitment on 26th April 2012 and has recruited 2362 patients, of whom 50 have Down syndrome, in the period up to 22nd February 2018. The study is open in 41 centres in UK and Ireland and included patients with both ALL and lymphoblastic lymphoma (LBL). The baseline characteristics of the patients recruited up to this date are shown in the table below. For DS-ALL, Day 29 MRD was available for 48 patients and was low risk in 25 cases (50%), risk in 19 (38 %) and no result was obtained in 4 (8 %). The therapy was generally well-tolerated, there have been no cases of therapy curtailment due to toxicity and only one patient due to receive intensified therapy per MRD risk assessment was unable to escalate due to toxicity. At a median follow-up of 32.7 months, there have been 4 events. These include two relapses (relapse rate: 4.1% (1.1-15.5) at 3 years) and two TRMs (one TRM in induction and the other in consolidation; both due to infection). Three year EFS is: 92.9% (95% CI: 79.1 - 97.7) with a three year OS of 95.9% (84.5 - 99.0). The remarkably low induction TRM for DS children on UKALL 2011 (1 death out of 50 patients, 2%), is comparable to that of non-DS children treated on the same protocol with a 3 drug induction (12 out of 1174 children, 1% induction TRM; induction TRM in DS-ALL vs non-DS-ALL p=0.42). It is also comparable to the induction TRM in DS-ALL noted in the latter half of the UKALL 2003 study (1/40, 2.5%) when the aforementioned treatment modifications were first implemented in the UK. Importantly, this TRM is a quarter of that when an historic cohort of DS-ALL children were treated with a 4-drug induction on our previous study (UKALL 2003, DS-ALL TRM 4/46 patients i.e. 8 %, p=0.19). Conclusion These preliminary results suggest that de-escalation of treatment is successful in reducing treatment related mortality for children with DS-ALL without increasing the risk of early relapse, however longer term follow-up is needed. Disclosures Ghorashian: Celgene: Other: travel support; Novartis: Honoraria. Hough:University College London Hospital's NHS Foundation Trust: Employment. Kearns:Pfizer: Consultancy, Research Funding; Galen: Research Funding. Vora:Jazz: Other: Advisory board; Medac: Other: Advisory board; Pfizer: Other: Advisory board; Amgen: Other: Advisory board; Novartis: Other: Advisory board.

scholarly journals Excellent Outcome of Children with Down Syndrome (DS) and Acute Lymphoblastic Leukemia (ALL) Treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocols 00-001 and 05-001

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 761-761
Author(s):  
Uma H. Athale ◽  
Maneka Puligandla ◽  
Kristen E. Stevenson ◽  
Barbara L. Asselin ◽  
Luis A. Clavell ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Acute Lymphoblastic Leukemia ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Event Free Survival ◽  
Free Survival ◽  
Children With Down Syndrome ◽  
Dana Farber Cancer Institute ◽  
Induction Failure

Abstract Background Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) are shown to have increased therapy-related morbidity and mortality. Hence, therapy modifications and/or dose-reductions are common treatment strategies for this patient (pt) population. Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols have used same risk-stratified treatment for children with and without DS and ALL. Aim: To define the toxicity profile and outcome of children with DS and de novo ALL treated on DFCI ALL Consortium therapy protocols 00-001 and 05-001 using therapy identical to non-DS patients. Methods: Demographic, clinical and outcome data of DS and non-DS patients enrolled on the DFCI ALL protocols 00-001 (2000-2004) and 05-001 (2005-2011) were analyzed. Risk categorization and protocol therapy have previously been described (J Clin Oncol 2013; 31:1202-10; Lancet Oncol 2015;16:1677-90). On both protocols, DS ALL pts were treated identically to non-DS pts without any dose reduction or modification, except for the option for DS ALL pts to receive 3 doses of leucovorin after IT methotrexate. Fisher's exact test was used to compare toxicities in the DS and non-DS pts and Gray test was used to compare the cumulative incidence of fracture and osteonecrosis. Overall survival (OS) was defined as time from registration to death. Event-free survival (EFS) was defined as time from registration to first event (defined as induction failure, relapse, second malignant neoplasm (SMN) or death due to any cause). Induction failure and induction death were included as events at time zero. Disease-free survival (DFS) was defined as time from complete remission (CR) to relapse, SMN or death. Pts without an event were censored at the last known follow-up. The Kaplan-Meier method was used for survival estimation and Greenwood's formula for calculation of 95% confidence interval (CI) of survival estimates. Outcome of DS patients was also examined using Ponte di Legno (PdL) risk group [Low risk (LR) was defined as age at diagnosis ≤ 6 yr. and white cell count < 10X109/L and, remainder as high risk (HR)].(Blood 2014;123:70-7). Two-sided p values <0.05 were considered significant. Results: Of 1286 eligible pts aged 1-18 yrs. with de novo ALL enrolled on protocols 00-001 and 05-001, 38 (3%) had DS. There was no difference in demographic or presenting clinical features between DS and non-DS ALL pts except immunophenotype (absence of T-ALL in DS vs 11.7% in non-DS, p=0.017) and presence of high hyperdiploidy (51-65 chromosomes) (8.8% in DS vs 25.1% in non-DS, p=0.027) (Table 1). Two DS-ALL pts withdrew from the study after achieving CR. There was no difference in the CR rates (DS: 100% vs non-DS: 95.2%, p=0.47) or proportion of pts with low end of induction minimal residual disease (MRD) between DS and non-DS groups (p=0.73). Toxicities were comparable except DS pts had significantly higher rates of ≥Grade 3 mucositis (data available for protocol 05-001 only) (DS: 52.0% vs. non-DS: 12.0%, p<0.001), non-CNS thrombosis/bleed (18.4% vs. 8.2%; p=0.036), and seizure (15.8% vs. 4.7%, p=0.010). DS pts also had marginally higher rate of bacterial and fungal infections (55.3% vs. 41.3%, p=0.096) (Table 2). All 38 DS pts achieved a CR and there were 4 relapses with 1 death due to disease. There were no treatment-related deaths in DS-ALL pts. With a median follow-up of 6.2 yrs. the 5-yr EFS, DFS, and OS of DS pts were similar to non-DS pts (90.7% [81.1-100.0] vs. 83.7% [81.7-85.9]; 90.7% [81.1-100.0] vs. 87.4% [85.5-89.3]; 97.1% [91.8-100.0] vs. 91.4% [89.8-93.0]), with the 95% CI overlapping for each comparison (Figures 1a and 1b). There was no difference in outcomes of DS-ALL PdL LR pts (n=13) compared to PdL HR pts (n=25) (5-yr EFS 90.0% [73.2-100.0]. vs. 91.0% [79.9-100.0]; 5-yr OS 100.0% [100.0-100.0] vs. 95.8% [88.2-100.0]). Conclusion: DS pts treated on DFCI ALL Consortium protocols without dose reduction or modifications achieved similar outcomes to non-DS pts. DS pts had a higher frequency of mucositis, infection, and seizures, but did not experience any treatment-related deaths. Other than a higher risk of thrombotic complications, they did not develop excessive toxicity to asparaginase. The low rates of relapse and toxicity-related mortality support the approach of unified therapy protocol for DS and non-DS ALL pts with emphasis on supportive care interventions to prevent toxicities. Overall and event free survival Overall and event free survival Disclosures Asselin: Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Sigma Tau Pharamceuticals: Consultancy.

scholarly journals Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia with kinase fusions in Taiwan

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yin-Chen Hsu ◽  
Chih-Hsiang Yu ◽  
Yan-Ming Chen ◽  
Kathryn G. Roberts ◽  
Yu-Ling Ni ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Acute Lymphoblastic Leukaemia ◽  
B Cell ◽  
Lymphoblastic Leukaemia ◽  
Kinase Inhibitors ◽  
Philadelphia Chromosome ◽  
Genetic Alterations ◽  
Childhood All ◽  
Free Survival ◽  
Polymerase Chain

AbstractPhiladelphia chromosome-like (Ph-like) acute lymphoblastic leukaemia (ALL), a high-risk subtype characterised by genomic alterations that activate cytokine receptor and kinase signalling, is associated with inferior outcomes in most childhood ALL clinical trials. Half of the patients with Ph-like ALL have kinase rearrangements or fusions. We examined the frequency and spectrum of these fusions using a retrospective cohort of 212 newly diagnosed patients with childhood B-cell ALL. Samples without known chromosomal alterations were subject to multiplex reverse transcription polymerase chain reaction to identify known Ph-like kinase fusions. Immunoglobulin heavy chain locus (IGH) capture and kinase capture were applied to samples without known kinase fusions. We detected known kinase fusions in five of 212 patients, comprising EBF1-PDGFRB, ETV6-ABL1, ZC3HAV1-ABL2, EPOR-IGH, and CNTRL-ABL1. Two patients with P2RY8-CRLF2 were identified. Patients with non-Ph kinase fusions had inferior 5-year event-free survival and overall survival compared with patients with other common genetic alterations. The prevalence of non-Ph kinase fusions in our Taiwanese cohort was lower than that reported in Caucasian populations. Future clinical trials with tyrosine kinase inhibitors may be indicated in Taiwan because of the inferior outcomes for B-cell ALL with kinase fusions.

scholarly journals Excess morbidity and mortality among survivors of childhood acute lymphoblastic leukaemia: 25 years of follow-up from the United Kingdom Childhood Cancer Study (UKCCS)

2021 ◽  
Author(s):  
Eleanor Kane ◽  
Sally Kinsey ◽  
Audrey Bonaventure ◽  
Tom Johnston ◽  
Jill Simpson ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Radiation Treatment ◽  
Absolute Risk ◽  
Later Life ◽  
Morbidity And Mortality ◽  
Childhood All ◽  
Risk Of Death ◽  
Childhood Acute Lymphoblastic Leukaemia

Objectives To examine morbidity and mortality in survivors of childhood acute lymphoblastic leukaemia (ALL) across their teenage and young adult (TYA) years; comparing the patterns observed with individually matched general population controls. Design Case-control study with follow-up linkage to administrative healthcare databases for up to 25 years. Setting The study population comprises all children (0-14 years) registered for primary care with the National Health Service (NHS) in England 1992-1996. Participants 1082 five-year survivors of ALL diagnosed <15 years of age, and 2018 age- and sex-matched population-based controls; followed to 15 March 2020. Main outcome measures Associations with hospital activity, cancer, and mortality were assessed using incidence rate ratios and absolute risk difference. Results Mortality 5-25 years after diagnosis was 20 times higher in cases than controls (Rate Ratio 21.3, 95% Confidence Interval 11.2-45.6), and cancer incidence 10 time higher (IRR 9.9 95% CI 4.1-29.1). Hospital activity was increased for many clinical specialties, the strongest effects being for endocrinology; outpatient IRR 36.7, 95% CI 17.3-93.4 and inpatient 19.7, 95% CI 1.9-25.5 for males, and 11.0, 95% CI 6.2-21.1 and 6.2 95% CI 3.1-13.5 respectively for females. Notable excesses were also evident for cardiology, neurology, ophthalmology, respiratory medicine and general medicine. Males were also more likely to attend gastroenterology, ENT (ear, nose and throat), urology, and dermatology; while females were more likely to be seen in plastic surgery and less likely in midwifery. Conclusions Adding to a large excess risk of death and cancer, survivors of childhood ALL experience excess outpatient and inpatient activity across their TYA years. Involving most clinical specialties, the observed effects are striking, showing no signs of diminishing over the first 25 years of follow-up. These findings underscore the need to take prior ALL drug and/or radiation treatment into account when interpreting seemingly unrelated symptoms in later life.

EXCESSIVE CHEMOTHERAPY-RELATED MYELOTOXICITY IN CHILDREN WITH DOWN SYNDROME AND ACUTE LYMPHOBLASTIC LEUKAEMIA

The Lancet ◽  
1986 ◽  
Vol 328 (8512) ◽  
pp. 914 ◽  
Author(s):  
Julie Blatt ◽  
Vincent Albo ◽  
William Prin ◽  
Salvatore Orlando ◽  
Michael Wollman
Keyword(s):  
Down Syndrome ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Children With Down Syndrome

Comparison of Long-Term Outcome Between Belgian and Vietnamese Children Treated for Acute Lymphoblastic Leukaemia According to the Same Protocol

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4292-4292
Author(s):  
Phuong Thu Vu Hoang
Keyword(s):  
United States ◽  
Acute Lymphoblastic Leukaemia ◽  
Regression Model ◽  
Lymphoblastic Leukaemia ◽  
East Asian ◽  
The United States ◽  
Relapse Free Survival ◽  
Childhood All ◽  
Free Survival ◽  
Risk Of Death

Abstract Abstract 4292 Introduction Acute lymphoblastic leukaemia (ALL) is the most common type of childhood cancer in East Asian, Caucasians and in the United States. Previous studies have shown poorer survival from childhood ALL among Asian compared to Caucasian populations. The US National Cancer Institute's Surveillance, Epidemiology and End Results program from 1998 to 2008 showed that poorer prognosis waseven observed in East Asian children living in the United States, compared to non-Hispanic Whites. This finding is interesting in that Asian ethnic groups are not socioeconomically disadvantaged in the United States relative to non-Hispanic whites as shown by US Census data. Aim The primary goal of this study was to compare the outcome of Belgian and Vietnamese children with ALL, treated with the same protocol (French acute lymphoblastic leukemia protocol FRALLE). Patients and Methods The Belgian series included 107 patients (aged less than 19 at diagnosis) followed at Cliniquesuniversitaires Saint-Luc (UCL), Brussels, Belgium between 2001 and 2011. The Vietnamese series included 166 patients from Blood Transfusion and Hematology Hospital, University of Medicine Pham Ngoc Thach (UPNT) at Ho Chi Minh city, Vietnam (aged less than 16 at diagnosis) and followed between 2005 and 2011. Clinical andbiologicalvariables and survival rates were compared using Cox Proportional Hazards Regression model. The association between clinicaland biological variables and both adverse drug reactions and relapse free survival were analyzed using Log-Binomial Regression model. All statistical analysis was performed using the ‘Epi’ and the ‘Survival’ package of the R 2.15.0 software. Results The two populations were comparable regarding age at diagnosis, sex ratio, initialwhite blood cell count, cytogenetic and steroid responsiveness at day 8. A higher prevalence of L2 type-ALL according to the FAB classification was found in Vietnamese children (81.3 % L2 in Vietnam vs 44.9% in Belgium). Vietnamese patients had a significantly lower survival than Belgian patients (p<0.001) (figure 1). In the multivariate analysis model, relative risk of death for Vietnamese children was 2.61 (95% CI= 1.03–6.65) (p = 0.04). Compared to the Belgian cohort, Vietnamese children had a lower relapse free survival (figure 2) and a higher relativerisk of relapse of 3.01 (95% CI = 1.53–5.93). They also disclosed a higher incidence of methotrexate-related grade 3 or 4 side effects (36.2% vs 5.6%). Conclusions Compared to Caucasians treated with the same protocol, a poorer overall survival was confirmed in children with ALL treated in Vietnam. Relapse free survival was lower and adverse reaction rate higher among Vietnamese children. Racial differences in pharmacogenetics of drugs as well as additional factors such as social status, lack of antibiotic prophylaxis or delayed access to care due to remoteness may explain these observations. Appendix Disclosures: No relevant conflicts of interest to declare.

scholarly journals Outcomes of treatment for relapsed acute lymphoblastic leukaemia in children with Down syndrome

2013 ◽  
Vol 162 (1) ◽  
pp. 98-106 ◽  
Author(s):  
Franziska Meyr ◽  
Gabriele Escherich ◽  
Georg Mann ◽  
Thomas Klingebiel ◽  
Andreas Kulozik ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Children With Down Syndrome
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