Need for new thinking: Treatment of relapsed leukemia in children with Down syndrome

Rabin, Karen R.; Izraeli, Shai; Hijiya, Nobuko

doi:10.1002/pbc.27644

Cited by 8 publications

(8 citation statements)

References 25 publications

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“…Chimeric antigen receptor (CAR)-T cells are also an attractive option for treating children with DS-ALL, and this category of patients is eligible for studies that assess the efficacy and safety of CAR-T cells (NCT02435849 trial), with the first published data indicating that the efficacy and toxicity profiles do not differ from those of ALL children without DS. [ 33 , 34 ]…”

Section: Discussionmentioning

confidence: 99%

“…However, at this time, it was considered important to conduct clinical trials to introduce immunotherapy to treat children with DS-ALL. [ 33 ]…”

Section: Discussionmentioning

confidence: 99%

“…Usually, children with DS and ALL are excluded from phase 1 and 2 studies with antileukemic agents based on the eligibility criteria (this is justified by the severe side effects observed in this group of patients). However, at this time, it was considered important to conduct clinical trials to introduce immunotherapy to treat children with DS-ALL [33] …”

Section: Discussionmentioning

confidence: 99%

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Outcomes of patients with Down syndrome and acute leukemia

Schmidt¹,

Coliţă

Ivanov

et al. 2021

Medicine

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Children with Down syndrome (DS) have a higher risk of developing acute leukemia than do those without DS. There are few studies in the literature about outcome, survival, and difficulties of treating patients with DS and acute leukemia in a developing country. This study aimed to analyze the outcome, response to treatment, survival, treatment complications, and causes of death in patients with DS and acute leukemia compared with those in patients with acute leukemia without DS diagnosed in the same period of time. We conducted a retrospective observational analysis including a cohort of 21 patients with DS and acute leukemia diagnosed between 2009 and 2018 in 3 hemato-oncology centers (2 pediatric centers and 1 adult hematology center). A group of patients with DS-acute lymphoblastic leukemia (DS-ALL) was analyzed and compared with a group of 165 patients with acute lymphoblastic leukemia without DS, and a group of patients with DS-acute myeloid leukemia (DS-AML) was analyzed and compared with a group of 50 patients with acute myeloid leukemia without DS, which was diagnosed during the same period of time (2009–2018) and treated under similar conditions in terms of both treatment protocols and economic resources. The overall survival rates in children with DS-ALL and DS-AML were 35.7% and 57.1%, respectively ( P = .438). The overall survival rate was significantly worse in children with DS-ALL than in those with acute lymphoblastic leukemia without DS (35.71% vs 75.80%, P = .001). We noted that treatment-related mortality in the patients with DS-ALL was high (50%) (infections and toxicities related to chemotherapy); this result was significantly different from that for patients with leukemia without DS ( P < .0001). The relapse rate was higher in patients with DS-ALL but not significantly higher than that in patients without DS ( P = .13). In contrast, the overall survival rate was better for patients with DS-AML than for those with acute myeloid leukemia without DS (57.1% vs 45.1%, P = .47). Because of the particularities of the host, we suggest that DS-ALL and DS-AML should be considered as independent diseases and treated according to specific protocols with therapy optimization per the minimal residual disease.

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Section: Discussionmentioning

confidence: 99%

“…However, at this time, it was considered important to conduct clinical trials to introduce immunotherapy to treat children with DS-ALL. [ 33 ]…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Outcomes of patients with Down syndrome and acute leukemia

Schmidt¹,

Coliţă

Ivanov

et al. 2021

Medicine

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“…Children with relapsed/refractory DS–ALL have been included in studies using tisagenlecleucel, with preliminary results identifying comparable safety and efficacy to children without DS [ 46 ]. Such findings highlight the importance of including children with DS in studies of new agents for the treatment of leukemia to identify innovative approaches to reduce rates of relapse and treat relapsed disease [ 47 ]. Novel therapeutic strategies targeting the somatic events found in DS leukemia or the mechanisms altered by trisomy 21 as the initiating event in DS leukemogenesis should also be explored, which ultimately may be applicable to a broad spectrum of hematological malignancies that present with a similar genetic background.…”

Section: Clinical Features Therapy and Outcome Of Ds-associated Leumentioning

confidence: 99%

Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome

2020

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Structural and numerical alterations of chromosome 21 are extremely common in hematological malignancies. While the functional impact of chimeric transcripts from fused chromosome 21 genes such as TEL-AML1, AML1-ETO, or FUS-ERG have been extensively studied, the role of gain of chromosome 21 remains largely unknown. Gain of chromosome 21 is a frequently occurring aberration in several types of acute leukemia and can be found in up to 35% of cases. Children with Down syndrome (DS), who harbor constitutive trisomy 21, highlight the link between gain of chromosome 21 and leukemogenesis, with an increased risk of developing acute leukemia compared with other children. Clinical outcomes for DS-associated leukemia have improved over the years through the development of uniform treatment protocols facilitated by international cooperative groups. The genetic landscape has also recently been characterized, providing an insight into the molecular pathogenesis underlying DS-associated leukemia. These studies emphasize the key role of trisomy 21 in priming a developmental stage and cellular context susceptible to transformation, and have unveiled its cooperative function with additional genetic events that occur during leukemia progression. Here, using DS-leukemia as a paradigm, we aim to integrate our current understanding of the role of trisomy 21, of critical dosage-sensitive chromosome 21 genes, and of associated mechanisms underlying the development of hematological malignancies. This review will pave the way for future investigations on the broad impact of gain of chromosome 21 in hematological cancer, with a view to discovering new vulnerabilities and develop novel targeted therapies to improve long term outcomes for DS and non-DS patients.

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“…Due to their poor outcomes with conventional intensive salvage therapy approaches, early use of CAR T-cell therapy as a curative strategy may be considered for this population (Table 2). The data available to date suggest that individuals with DS tolerate immunotherapies well with efficacy and toxic effects profiles similar to those without DS …”

Section: Treatment Of Relapsementioning

confidence: 99%

Management of Down Syndrome–Associated Leukemias

et al. 2023

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ImportanceDown syndrome (DS), caused by an extra copy of material from chromosome 21, is one of the most common genetic conditions. The increased risk of acute leukemia in DS (DS-AL) has been recognized for decades, consisting of an approximately 150-fold higher risk of acute myeloid leukemia (AML) before age 4 years, and a 10- to 20-fold higher risk of acute lymphoblastic leukemia (ALL), compared with children without DS.ObservationsA recent National Institutes of Health-sponsored conference, ImpacT21, reviewed research and clinical trials in children, adolescents, and young adults (AYAs) with DS-AL and are presented herein, including presentation and treatment, clinical trial design, and ethical considerations for this unique population. Between 10% to 30% of infants with DS are diagnosed with transient abnormal myelopoiesis (TAM), which spontaneously regresses. After a latency period of up to 4 years, 20% to 30% develop myeloid leukemia associated with DS (ML-DS). Recent studies have characterized somatic mutations associated with progression from TAM to ML-DS, but predicting which patients will progress to ML-DS remains elusive. Clinical trials for DS-AL have aimed to reduce treatment-related mortality (TRM) and improve survival. Children with ML-DS have better outcomes compared with non-DS AML, but outcomes remain dismal in relapse. In contrast, patients with DS-ALL have inferior outcomes compared with those without DS, due to both higher TRM and relapse. Management of relapsed leukemia poses unique challenges owing to disease biology and increased vulnerability to toxic effects. Late effects in survivors of DS-AL are an important area in need of further study because they may demonstrate unique patterns in the setting of chronic medical conditions associated with DS.Conclusions and RelevanceOptimal management of DS-AL requires specific molecular testing, meticulous supportive care, and tailored therapy to reduce TRM while optimizing survival. There is no standard approach to treatment of relapsed disease. Future work should include identification of biomarkers predictive of toxic effects; enhanced clinical and scientific collaborations; promotion of access to novel agents through innovative clinical trial design; and dedicated studies of late effects of treatment.

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Need for new thinking: Treatment of relapsed leukemia in children with Down syndrome

Cited by 8 publications

References 25 publications

Outcomes of patients with Down syndrome and acute leukemia

Outcomes of patients with Down syndrome and acute leukemia

Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome

Management of Down Syndrome–Associated Leukemias

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