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Transient Self-Limited Leukemia: The Intrigue of Down Syndrome–Associated Leukemias

December 11, 2022

There is more than a 100-fold and 30-fold risk, respectively, of developing acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) in individuals with Down syndrome compared to the general population. In 2022, this very topic took center stage as Dr. Irene Roberts from the Weatherall Institute of Molecular Medicine delivered the Ham-Wasserman lecture.

Dr. Roberts discussed myeloid leukemia of Down syndrome (ML-DS), which generally occurs in children younger than five years and can present after an episode of transient abnormal myelopoiesis (TAM) that often spontaneously regresses with supportive care such as transfusion. TAM occurs in a multistep process provoked by trisomy 21–associated abnormal fetal hematopoiesis, with acquired somatic mutations in GATA1, which is located on the X chromosome. TAM begins in utero and often presents in newborns as a self-limiting leukemic syndrome that usually resolves without intervention in three to four months.

Around 10 percent of newborns with Down syndrome will have clinical signs of TAM; however, silent mutations in GATA1 occur at a higher frequency (~30%). It is unknown why GATA1 mutations are acquired prenatally in this population. Some have postulated a mutagenic phenotype associated with trisomy 21 with defects in DNA repair, though evidence is limited. Alternatively, this may represent an adaptive mechanism and selective advantage of hematopoietic cells in aneuploidy.

While 80 to 90 percent of newborns with TAM enter spontaneous remission, some higher-risk patients (5-20%) benefit from early cytarabine-based treatment. Early death results from pre-term delivery, hyperleukocytosis (white blood cell count >100 × 109/L), liver/organ involvement, and coagulopathy. Approximately 20 percent of patients with TAM develop ML-DS in clones that persist and through acquisition of secondary mutations, most often involving the cohesion complex. Treatment of TAM has not been shown to prevent the development of ML-DS, and the decision to treat can be challenging. Residual disease at three months after diagnosis of TAM by flow cytometry or molecular methods is associated with an increased risk for developing ML-DS. Importantly, those with resolution of TAM may still develop ML-DS and should be carefully monitored.

ML-DS tends to be chemoresponsive, with overall favorable prognosis with reduced doses of cytarabine-containing chemotherapy required to mitigate toxicity (myelosuppression, infection, and cardiotoxicity). In most studies, approximately 90 percent will achieve both event-free survival and overall survival (OS) at five years; however, outcomes of relapsed/refractory ML-DS are relatively poor, with higher treatment-related toxicity and poor survival after hematopoietic stem cell transplantation. In a Center for International Blood and Marrow Transplant Research analysis, three-year probability of OS, with transplant was only 19 percent. In recent years, minimal residual disease by multiparameter flow cytometry at the end of induction therapy has been predictive of outcomes in these patients.

Dr. Roberts also described the linkage between trisomy 21 and ALL. Unlike ML-DS, outcomes of ALL in Down syndrome (DS-ALL) are inferior to those of the general population, with higher treatment-related toxicity and more aggressive disease biology. Interestingly, DS-ALL is predominantly a B-cell disease, lacking favorable cytogenetics (ETV6-RUNX1 and high hyperdiploidy), BCR:ABL translocations, and KMT2A gene rearrangements. Most commonly, DS-ALL is characterized by cytokine receptor–like factor 2 rearrangements with co-occurring JAK2- and RAS-activating mutations. Trisomy 21 has been linked to the impairment of fetal B-progenitor cells due to intrinsic defects and extrinsic factors associated with the hematopoietic microenvironment. There has not been a defined prenatal stage of DS-ALL, as this condition is rare in children younger than 12 months. 

Before this session, I shared my story with Dr. Roberts. My 37-year-old sister, is now 34 years out from ML-DS, which is, as Dr. Roberts said it best, “such a nice reminder of why we all go to work every day!” We will never fully know the depth of those we impact. Here is a picture of my sister Emy, who doesn’t mind the fame.


Dr. Blackmon and Dr. Amanam indicated no relevant conflicts of interest.

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