To the Editor, Children with Down syndrome (DS) have increased risk of leukemia, most commonly B-cell acute lymphoblastic leukemia (B-ALL) 1. In contrast, T-cell acute lymphoblastic leukemia (T-ALL) is rare with DS. In a cohort of 343 pediatric T-ALL patients, only 8 (1.8%) had DS 2. Similarly, in 708 patients compiled with DS and ALL, only five patients (0.7%) had T-ALL 3. While outcomes for DS patients with B-ALL have improved, and as T-ALL in DS is rare and T-lymphoblastic lymphoma (T-LLy) in DS has not previously been reported, uncertainty persists. We collaborated with international colleagues on a patient with DS and T-LLy and herein report the case. A 5-year-old boy with DS presented with left-sided Horner syndrome and cough for 3 weeks. Evaluated by ophthalmology for anisocoria, chest imaging was recommended to evaluate unilateral miosis and ptosis. Computed tomography (CT) revealed an anterior mediastinal mass measuring 9.7 cm × 10.5 cm × 15.7 cm (anteroposterior × transverse × craniocaudal) (Figure 1A). He was admitted to the pediatric intensive care unit due to airway compression and pericardial effusion. Needle aspiration of the mass enabled flow cytometry, which revealed a CD45+ population, with positivity for CD7/CD8, partial positivity for CD4/CD34, negativity for CD19 and surface CD3, collectively indicating T-LLy. Cerebrospinal fluid and bone marrow were negative for malignancy. A baseline positron emission tomography (PET) scan was deemed unsafe given the tenuous respiratory status. He was treated with 24 h of intravenous (IV) methylprednisolone, secondary to urgent need for respiratory stability, prior to beginning treatment per Children's Oncology Group (COG) study AALL1231 (NCT02112916) 4. The patient was admitted throughout induction due to high risk of toxicity. Horner syndrome resolved within 2 weeks. End of induction PET scan demonstrated partial response to chemotherapy with residual soft tissue density extending from the midline anterior mediastinum into the left upper mediastinum with low-level fludeoxyglucose (FDG) uptake (SUV 1.7, Deauville 2) (Figure 1B). He continued per the standard risk arm of AALL1231 and achieved PET-negative complete remission at the end of consolidation (Figure 1C). Due to the potential for increased toxicities in patients with DS, we followed the standard risk arm of COG study AALL1231, thereby avoiding the known toxicities of HD-MTX (Figure S1). Additionally, as metabolism and toxicity profiles of bortezomib and nelarabine were not studied in patients with DS, they were not utilized 5. Leucovorin was utilized with IT MTX to prevent toxicity. Treatment was complicated by grade 2 disordered thiopurine metabolism, requiring a 70% reduction in 6-mercaptopurine dose with the addition of allopurinol. Leucovorin was given with IT MTX to prevent further toxicity. Induction therapy was complicated by hyperuricemia requiring rasburicase; need for high-flow oxygen; and febrile neutropenia treated with empiric cefepime for 5 days, followed by levofloxacin prophylaxis until neutropenia resolved, and micafungin prophylaxis while on dexamethasone. Consolidation was complicated by Staphylococcus aureus (methicillin-sensitive) bacteremia, grade 3 mucositis requiring IV opiates, pancytopenia requiring transfusions, total parenteral nutrition, and gastrostomy for nutritional support. There were no complications during the interim maintenance phase. During delayed intensification, our patient received a 10-day course of levofloxacin for gastrostomy cellulitis, but did not require admission. During maintenance, the patient developed abdominal pain, nausea, vomiting, bruxism, polydipsia, hypoglycemia, and hyperbilirubinemia. Thiopurine metabolites were significantly elevated at that time: 6-methylmercaptopurine (MMP) of 41,278 µmol/8 × 108 (normal range ≤ 5700), 6-thioguanine (TG) of 255 µmol/8 × 108 RBC (normal 235–450). Pharmacogenetic assessment of TPMT and NUDT15 genotype did not predict abnormal thiopurine metabolism. Accurate adherence to the medication was assumed given the parent's mastery of the treatment plan, but could not be definitively proven. The patient's mercaptopurine dose was reduced to 30% of standard dosing and allopurinol added. MMP, TG, glucose, and bilirubin levels all normalized with this intervention and maintenance completed without recurrence of symptoms. In maintenance cycle 5, the patient developed fever (103°F), pruritic rash, and hypoxia. Chest radiograph demonstrated pneumonia, and respiratory pathogen testing was positive for respiratory syncytial virus, rhinovirus/enterovirus. The patient was hypogammaglobulinemic (251 mg/dL, normal 542–1358), yet not neutropenic, and hospitalized for high-flow oxygen therapy, empiric antimicrobials, intravenous immunoglobulin (IVIG), and dexamethasone. Oral mercaptopurine was held for 2 days as a precaution and subsequently resumed. Our patient's significant infectious toxicities during induction, consolidation, delayed intensification, and cycle 5 of maintenance are notable, as non-DS patients treated on the standard-risk, non-investigational arm of AALL1231 only rarely experienced similar occurrences: sepsis only occurred in 4.5% of patients in consolidation, and grade 3–4 infections during maintenance were uncommon 4. Yet, our patient's clinical course demonstrates that with treatment modifications and supportive care, such as avoidance of known toxicity-inducing medications (e.g., HD-MTX), avoidance of potentially toxic medications, even those presumed to be efficacious (e.g., nelarabine and bortezomib), as well as prophylactic in-patient monitoring and symptomatic support, successful treatment is possible. Our patient remains clinically well and in remission, now more than 34 months following the completion of therapy. While our patient received traditional therapy, in the short time since we treated this patient, there have been significant developments in diagnostics and therapeutics of DS-ALL, which may have implications for future DS-LLy patients 6, 7. Genomic studies of DS B-ALL have identified distinctive alterations that may be therapeutically targetable 8. Similar studies are needed in T-ALL and T-LLy, but are challenging due to the rarity in children with DS. Promising results of novel non-toxic therapies amenable for children with DS and B-ALL provide optimism that options may become available for children with DS and T-LLy, and may provide improved outcomes with a lower burden of treatment-related toxicity 9-12. Per local institutional review board (IRB) guidelines, a waiver of IRB review was granted for this retrospective single case report. The authors do wish to thank the family of the patient presented for their willingness to share and publish the clinical course; they provided consent to do so. The patient was not enrolled on a clinical trial, so no clinical study registration number is available. The authors declare no conflicts of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Tape et al. (Tue,) studied this question.
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