Patient 2
A 3-year-old male with CD33+ AML received upfront therapy on AAML1031 Arm B (bortezomib arm), and relapsed with a scalp chloroma seven months post-diagnosis. He was re-induced (Table 1), but following re-induction a BMBA demonstrated 35% blasts. He then received clofarabine, topotecan, thiotepa, and vinorelbine, and his MRD decreased to 1%. He underwent unrelated donor peripheral stem cell transplant (PSCT) followed by azacytidine for nine cycles before developing a maxillary sinus chloroma and 33% marrow involvement with CD33+ myeloid blasts. This second relapse prompted the decision to pursue GO.
A pre-GO ECHO showed normal LVEF of 60% and LVSF of 31% (Figure 1). He received GO (3 mg/m2/dose) on days 1, 4, and 8 with concurrent radiotherapy for the chloroma. BMBA on day 11 showed hypocellularity without leukemic blasts. He received two additional doses of GO on days 15 and 18 for 15mg/m2 total. He then developed respiratory distress, hypotension, altered mental status, and a distended abdomen requiring transfer to the intensive care unit (ICU) while afebrile with negative blood cultures. An ECHO showed a severely diminished LVEF of 21%, LVSF of 12%, and mild LV dilation. An abdominal ultrasound (AUS) showed hepatomegaly but normal portal venous flow. Labwork showed a BNP of 6373 pg/mL and a bilirubin that peaked at 2.9 mg/dL. He was started on dobutamine, milrinone, and epinephrine for cardiogenic shock. His epinephrine and dobutamine were stopped after 2 days, milrinone was stopped after 14 days, and he initiated enalapril and spironolactone. His LVEF improved to 55%, and LVSF to 29% within 12 days of the ICU transfer. A BMBA two months post-GO remained MRD negative, and an ECHO three months post-GO showed stable LV function.  As a bridge to a second SCT, he received a cycle of decitabine.
4 months following GO, he underwent BMT. On day +16 he developed hepatomegaly and a new cardiac gallop; ECHO showed a decrease in LVEF to 45% and LVSF to 25%, his BNP was 8167pg/ml, and he was transferred to the ICU where furosemide and milrinone were started. AUS showed hepatomegaly with normal flow in the portal vein. Five days later, milrinone was stopped and within 1 week his BNP trended down to 396 and his LVEF and LVSF normalized. 50 days post-BMT an ECHO and BNP were repeated and remained normal. Unfortunately, 21 months post-BMT, he had a bone marrow/extramedullary relapse and died 3 months later.
DISCUSSION We present vignettes of two pediatric patients with r/r AML who developed acute LV dysfunction following 15-18mg/m2 of fractioned GO monotherapy, suggesting a potential relationship between GO and cardiotoxicity in pre-treated AML patients. Both patients had significant prior anthracycline exposure but low-normal to normal cardiac function before GO administration. Their cardiac dysfunction was characterized by severely decreased systolic and diastolic function, elevated BNPs, and improvement with medical therapy.
Patient 2 was critically ill without alternative clinical explanation when LVSD was identified while Patient 1 was initially asymptomatic, suggesting the utility of routine ECHO monitoring in patients with AML receiving GO-monotherapy at these doses. Both patients achieved remission following three 3mg/m2 doses of GO, tolerated full-intensity SCT, did not develop SOS, and maintained post-SCT remissions for 9 months and counting for Patient 1, and 21 months for Patient 2. Given that fractionation was hypothesized to reduce toxicity from GO, it is important to note that the cardiac toxicity encountered at doses of 15-18mg/m2 was not prevented by fractionation, although SOS did not occur and toxicity did not preclude SCT. While cardiotoxicity is not commonly described with GO, this and prior reports of worsening LVSF following GO2,5 suggest the need for cardiac surveillance following GO administration. Future studies evaluating cardiotoxicity following GO may deepen our understanding of this clinically important toxicity and guide optimal monitoring strategies for these patients.
ACNKOWLEDGEMENTS
We would like to thank all that contributed to and supported this project. KM reviewed the medical histories, wrote and revised the manuscript, created the table and figure. KG compiled echocardiogram data. KG, KO, AS, and BO provided critical revisions to the manuscript. RA conceptualized the project, provided guidance on the development of the manuscript, and provided revisions. No authors have conflicts of interest to disclose.
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TABLE 1 Legend: