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

Abstract

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.

High Disease-Free Survival with Enhanced Protection against Relapse after Double-Unit Cord Blood Transplantation When Compared with T Cell–Depleted Unrelated Donor Transplantation in Patients with Acute Leukemia and Chronic Myelogenous Leukemia

“…Platelet recovery was also delayed when compared to URDT recipients, although in patients alive at day 100 all but one recovered platelets indicating that failed platelet engraftment is a manifestation of early TRM. In this ATG-free platform, while rates of chronic GVHD were low as previously reported 22,30–32 , the acute GVHD incidence was 55% supporting the current investigation of measures to mitigate severe acute GVHD after DCBT 22,33–36 .…”

Child and adolescent Down syndrome-associated leukaemia: the Irish experience

“…As is characteristic, our DS-ALL cohort spanned a broad age range, although there were no cases of infantile leukaemia. In agreement with other cohorts of DS-ALL, we observed the following: white cell count at diagnosis was low (median 5.7 9 10 9 /L); favourable ALL-associated recurrent cytogenetic abnormalities (t [12,21], hyperdiploidy) were only present in a minority of patients (30 %); all leukaemias were of B cell lineage and the majority of patients (53 %) (Fig. 2) shows that 63 % of our cohort remains alive, with a median follow-up of 3.6 years (range 0.04-6.3 years).…”

“…More attention to supportive care, prophylactic antibiotics, immunoglobulin replacement therapy and earlier aggressive management of infectious complications are applicable to both leukaemias in Down's patients [12].…”

“…It has a worse prognosis than childhood and young adolescent ALL [7][8][9][10][11][12][13]. Features of DS-ALL are compared to those of childhood ALL in Table 3.…”

Evaluation of ETV6/RUNX1 Fusion and Additional Abnormalities Involving ETV6 and/or RUNX1 Genes Using FISH Technique in Patients with Childhood Acute Lymphoblastic Leukemia

“…This patient relapsed 42 months after diagnosis and patient died due to developing sepsis. Children with Down syndrome have an increased risk for developing B-cell precursor ALL and an poor outcome due to a high relapse rate and the increased adverse effects of chemotherapy [30]. Two patients had RUNX1 gene amplification together with ETV6-RUNX1 fusion (Case #11 and 12).…”