Outcomes of treatment for relapsed acute lymphoblastic leukaemia in children with <scp>D</scp>own syndrome

Meyr, Franziska; Escherich, Gabriele; Mann, Georg; Klingebiel, Thomas; Kulozik, Andreas E.; Schrappe, Martin; Henze, Günter; Stackelberg, Arend von

doi:10.1111/bjh.12348

Cited by 31 publications

(29 citation statements)

References 36 publications

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“…[23][24][25]33 Historically, Down syndrome ALL (DS-ALL) has been associated with inferior outcome, both with regard to OS and EFS. 34,35 In this study, DS-ALL was associated with very poor outcome, irrespective of the time period (early vs. late period) and the fact that most of these patients were stratified as standard-risk. Second relapses were the most common reason for treatment failure, indicating that patients with relapsed DS-ALL might have been treated with less intensive post-induction regimens to minimize the risk of treatment toxicity but subsequently failed to remain in long-term second remission.…”

Section: Discussionmentioning

confidence: 60%

“…36 In a study by Meyr et al, children with DS had worse outcome after relapse mainly because of increased toxicity rather than subsequent relapse, but if the relapse occurred after the year 2000 this difference was not maintained. 35 Adverse clinical factors, such as the time to relapse, age 37,38 and WBC 39 and cytogenetic risk factors, 17,18,20 are most likely surrogate markers for underlying submicroscopic genetic abnormalities. [40][41][42] With increased understanding of the biology of ALL, genetic factors are expected to be included in the future risk stratification and serve as targets for novel therapies.…”

Section: Discussionmentioning

confidence: 99%

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Relapsed childhood acute lymphoblastic leukemia in the Nordic countries: prognostic factors, treatment and outcome

et al. 2015

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R elapse is the main reason for treatment failure in childhood acute lymphoblastic leukemia. Despite improvements in the up-front therapy, survival after relapse is still relatively poor, especially for high-risk relapses. The aims of this study were to assess outcomes following acute lymphoblastic leukemia relapse after common initial Nordic Society of Paediatric Haematology and Oncology protocol treatment; to validate currently used risk stratifications, and identify additional prognostic factors for overall survival. Altogether, 516 of 2735 patients (18.9%) relapsed between 1992 and 2011 and were included in the study. There were no statistically significant differences in outcome between the up-front protocols or between the relapse protocols used, but an improvement over time was observed. The 5-year overall survival for patients relapsing in the period 2002-2011 was 57.5±3.4%, but 44.7±3.2% (P<0.001) if relapse occurred in the period 1992-2001. Factors independently predicting mortality after relapse included short duration of first remission, bone marrow involvement, age ten years or over, unfavorable cytogenetics, and Down syndrome. T-cell immunophenotype was not an independent prognostic factor unless in combination with hyperleukocytosis at diagnosis. The outcome for early combined pre-B relapses was unexpectedly poor (5-year overall survival 38.0±10.6%), which supports the notion that these patients need further risk adjustment. Although survival outcomes have improved over time, the development of novel approaches is urgently needed to increase survival in relapsed childhood acute lymphoblastic leukemia. Relapsed childhood acute lymphoblastic leukemia in the Nordic countries: prognostic factors, treatment and outcome

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Relapsed childhood acute lymphoblastic leukemia in the Nordic countries: prognostic factors, treatment and outcome

et al. 2015

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“…Despite children with relapsed DS-ALL having more favorable prognostic factors than relapsed NDS-ALL, 52 the prognosis of relapse of DS-ALL is grim. A recent study analyzing the outcome of 49 DS-ALL patients treated on the BFM relapse protocol 52 demonstrated only 17% long-term survival, with TRM being the major factor determining the worse prognosis compared with NDS-ALL.…”

Section: Treatment Of Relapsementioning

confidence: 99%

“…A recent study analyzing the outcome of 49 DS-ALL patients treated on the BFM relapse protocol 52 demonstrated only 17% long-term survival, with TRM being the major factor determining the worse prognosis compared with NDS-ALL. There is a general reluctance to use stem cell transplantation (SCT), because this therapy is considered to be too toxic.…”

Section: Treatment Of Relapsementioning

confidence: 99%

How I treat ALL in Down's syndrome: pathobiology and management

Izraeli

Vora

Zwaan

et al. 2014

Blood

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Children with Down syndrome are at high risk for developing B-cell precursor acute lymphoblastic leukemia (DS-ALL) associated with poor outcome due to both a high relapse rate and increased treatment-related mortality (TRM) from infections. Biologically, these heterogeneous leukemias are characterized by under-representation of the common cytogenetic subgroups of childhood ALL and overrepresentation of CRLF2-IL7R-JAK-STAT activating genetic aberrations. Although relapse is the major determinant of poor outcomes in this population, de-escalation of chemotherapy intensity might be feasible in the 10% to 15% DS-ALL patients with ETV6-RUNX1 or high hyperdipoidy in whom TRM is the major limiting event. As infection-associated TRM occurs during all treatment phases, including the maintenance period, increased surveillance and supportive care is required throughout therapy. Improvement in outcome will require better understanding of the causes of treatment failure and TRM, incorporation of new therapies targeting the unique biological properties of DS-ALL, and enhanced supportive care measures to reduce the risk of infection-related TRM. To facilitate these goals, an international collaboration plans to establish a prospective DS-ALL registry and develop specific supportive care recommendations for this at-risk population.

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“…53 The large size of our cohort enabled the observation that the increased TRM is present throughout treatment, with about half of the deaths occurring during maintenance therapy. While doses of myelosuppressive chemotherapy are typically adjusted during maintenance therapy, to maintain an adequate neutrophil count, this phase of treatment may nevertheless lead to B-cell depletion and hypogammaglobulinemia, and hence to a higher infection rate in already immunecompromised DS patients.…”

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confidence: 96%

Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group

Buitenkamp

Izraeli

Zimmermann³

et al. 2014

Blood

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Key Points• Although the risk of ALL relapse is significantly higher in children with DS, goodprognosis subgroups have been identified. • Patients with DS-ALL have higher treatment-related mortality throughout the treatment period independent of the therapeutic regimen.Children with Down syndrome (DS) have an increased risk of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). The prognostic factors and outcome of DS-ALL patients treated in contemporary protocols are uncertain. We studied 653 DS-ALL patients enrolled in 16 international trials from 1995 to 2004. Non-DS BCP-ALL patients from the Dutch Child Oncology Group and Berlin-Frankfurt-Münster were reference cohorts. DS-ALL patients had a higher 8-year cumulative incidence of relapse (26% 6 2% vs 15% 6 1%, P < .001) and 2-year treatment-related mortality (TRM) (7% 6 1% vs 2.0% 6 <1%, P < .0001) than non-DS patients, resulting in lower 8-year event-free survival (EFS) (64% 6 2% vs 81% 6 2%, P < .0001) and overall survival (74% 6 2% vs 89% 6 1%, P < .0001). Independent favorable prognostic factors include age <6 years (hazard ratio [HR] 5 0.58, P 5 .002), white blood cell (WBC) count <10 3 10 9 /L (HR 5 0.60, P 5 .005), and ETV6-RUNX1 (HR 5 0.14, P 5 .006) for EFS and age (HR 5 0.48, P < .001), ETV6-RUNX1 (HR 5 0.1, P 5 .016) and high hyperdiploidy (HeH) (HR 5 0.29, P 5 .04) for relapse-free survival. TRM was the major cause of death in ETV6-RUNX1 and HeH DSALLs. Thus, while relapse is the main contributor to poorer survival in DS-ALL, infection-associated TRM was increased in all protocol elements, unrelated to treatment phase or regimen. Future strategies to improve outcome in DS-ALL should include improved supportive care throughout therapy and reduction of therapy in newly identified good-prognosis subgroups. (Blood. 2014; 123(1):70-77)

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

Cited by 31 publications

References 36 publications

Relapsed childhood acute lymphoblastic leukemia in the Nordic countries: prognostic factors, treatment and outcome

Relapsed childhood acute lymphoblastic leukemia in the Nordic countries: prognostic factors, treatment and outcome

How I treat ALL in Down's syndrome: pathobiology and management

Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group

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