CASE PRESENTATION
A 30 year-old male with Down syndrome presented with fever, cough, and shortness of breath in November 2013. He was managed in our pediatric unit because of current favorable outcomes for Adolescents and Young Adults (AYA) with ALL treating with pediatric COG protocols.11 His complete blood count (CBC) showed pancytopenia with a white blood cell (WBC) count of 1.4 x 10^9/L, hemoglobin of 8.3 g/dL, and platelet count of 32 x 10^9/L with occasional circulating blasts. Bone marrow aspirate and biopsy confirmed the diagnosis of acute lymphoblastic leukemia with 73% blasts which co-expressed CD34, CD19, CD10 and TdT with aberrant expression of dim CD33 by flow cytometry, which was consistent with B-precursor ALL. Cytogenetic analysis was not successful but FISH from a bone marrow sample obtained on day 17 during Induction chemotherapy as per the Children’s Oncology Group (COG) study AALL1131 showed nuc ish(ETV6x2,RUNX1x3)[250] which was a normal signal pattern for constitutional trisomy 21 with two ETV6 signals and three RUNX1 signals. Diagnostic cerebrospinal fluid was negative for blasts.
The patient was treated per COG high risk protocol AALL1131, Down syndrome arm due to NCI risk factor for age above 10 years old. He had a rapid early response with a M1 marrow at Day 17 and he achieved complete remission after Induction with negative minimal residual disease (MRD). He had a complicated treatment course including a few episodes of sepsis, one of which included multi-organ failure for which he was in the Medical ICU, and PICC line associated DVT, Following the end of his treatment, his platelet count never normalized and ranged between 90x10^9/L and 112x10^9/L. At his lowest level of thrombocytopenia to 48x10^9/L in September 2017, which was four years after the initial diagnosis, a repeat bone marrow aspirate and biopsy was obtained and showed a 90% cellular bone marrow with 82% blasts, consistent with late bone marrow relapse. FISH showed CRLF2 translocation positive in 63.5% of cells and was also positive for deletion of CDKN2A on chromosome 9p beside his constitutional trisomy of chromosome 21. CNS was negative. This relapse was treated with Reinduction chemotherapy per ALL R3 protocol (Dexamethasone 20mg/m2/day day 1-5 & 15-19, Mitoxantrone 10mg/m2/dose day 1-2, Vincristine 1.5mg/m2/dose from day 3, then weekly; PEG-asparaginase 2500U/M2 day 3 and 18; Intrathecal Methotrexate day 1 and 8). Post-reinduction day 29 MRD was 0.2% (Table 1).
He continued to receive Consolidation chemotherapy per ALL R3 protocol (Intrathecal Methotrexate day 1, Dexamethasone 6mg/m2/day day 1-5, methotrexate 1000mg/m2/dose day 8 with Leucovorin rescue, Vincristine 1.5ng/m2/dose day 3, PEG-asparaginase 2500U/m2/dose day 9, Cyclophosphamide 440mg/m2/dose day 15-19, Etoposide 100mg/m2/dose day 15-19), after which his bone marrow had negative MRD. While hospitalized for Intensification chemotherapy, he developed sepsis, necrotizing pneumonia, and severe bilateral pleural effusions. BAL revealed Candida albicans. CT imaging also revealed near complete splenic infarct, right renal perfusion deficits with signs of liquefaction and a segmental area of abnormal small bowel wall enhancement and concern for focal small bowel wall defect. He also developed delirium related to his severe illness and prolonged hospitalization. Due to severe illness, his chemotherapy was held during a three month period. A bone marrow after three months continued to demonstrate negative MRD. Once he became more clinically stable, chemotherapy was attempted with intermediate dosed Methotrexate but this hospital course was complicated by infection necessitating removal of his broviac, fluid overload, and a persistent cavitary lung lesion. At this point, a decision was made by his family and treatment team to stop chemotherapy. About 50 weeks after his diagnosis of relapsed disease, a repeat bone marrow continued to demonstrate negative MRD. He was followed closely as an outpatient. Unfortunately, he presented with acute onset psychosis and thrombocytopenia about 2 years after stopping his treatment and bone marrow was consistent with relapsed disease. Family opted for no further therapy and unfortunately the patient passed away 7 weeks later.