Case Description
A 14-year-old Caucasian girl with late relapse pre-B-cell ALL with amplified RUNX1 (iAMP21 mutation) developed sudden hyperbilirubinemia 31 days following a matched unrelated umbilical cord transplant (UCBT). Prior to receiving her UCBT, she underwent extensive chemotherapy (including inotuzimab and vincristine, among others) and chimeric antigen receptor T cell (CAR-T) therapy leading to a diagnosis of complex regional pain syndrome. She had no evidence of disease on +25 days post-HCT bone marrow evaluation and remained 100% donor in her bone marrow by chimerism. She had undergone chemotherapy conditioning with CY, fludarabine and total body irradiation with post-HCT complications including persistent nausea, mucositis, presumed fungal pneumonia treated with voriconazole and micafungin, breakthrough menstrual bleeding (despite leuprolide acetate depot prior to conditioning therapy) managed with estradiol daily and dysuria and frequency concerning for HC. Urine studies revealed BK viruria and serum studies were positive but not quantifiable for viremia. Although her nausea and mucositis largely resolved with count recovery on day 21, she continued to experience lingering dysuria and hematuria with small clots concerning for persistent HC. She received additional fluids with phenazopyridine (every 6 hours), oxybutynin (every 6 hours) and oxycodone for symptomatic control of dysuria.
About 2 weeks after the onset of HC (post HCT day 28), total bilirubin was noted to be 5.5 mg/dL (normal 0.2-1.3 mg/dL) with a direct bilirubin of 4.4 mg/dL (normal 0.0-0.2 mg/dL) on routine outpatient follow-up. She underwent an abdominal ultrasound which revealed cholelithiasis without evidence of cholecystitis and hepatomegaly with normal grayscale and doppler evaluation. Her hemoglobin was stable at 9.7 g/dL (normal 11.7-15.7 g/dL) from 10 g/dL the week prior following a red blood cell transfusion. A peripheral blood smear revealed slight normochromic normocytic anemia with red cell regeneration, rare spherocytes (consistent with history of recent red blood cell transfusion), and rare “bite” cells raising the possibility of oxidant hemolysis (Figure 1A). An LDH was elevated at 379 U/L. A direct Coomb’s test was negative. The differential diagnosis based on the peripheral blood smear included G6PD deficiency, severe liver disease, and congenital unstable hemoglobin. Clinical considerations with elevated direct hyperbilirubinemia included post-transplant sinusoidal obstruction syndrome, cholelithiasis and transient TPN-induced hyperbilirubinemia. She had normal coagulation markers (INR, PTT, fibrinogen). As a precaution given cholecystitis, she was restarted on ursodiol at 10 mg/kg/daily. Further testing was negative for above mentioned differential.
One week later (post HCT day 34), she continued to have persistent but indirect hyperbilirubinemia (total bilirubin 2.3 mg/dL, indirect bilirubin 2.1 mg/dL), increasing absolute reticulocyte count (195.8 x109/L) and now rapidly declining hemoglobin (7.6 g/dL) requiring 2 units of red blood cell transfusion. The LDH was 341 U/L. The differential included transplant associated thrombotic microangiopathy (TA-TMA), immune mediated cytopenia, medication induced hemolysis (she was also on sulfamethoxazole/trimethoprim which was started a week prior) or evolving acute graft versus host disease (aGVHD). A repeat peripheral blood smear obtained prior to the transfusion was reported as showing overall normocytic marked anemia with ”bite,” ”veil,” and ”apple core” red cells along with morphologic evidence of increased red cell regeneration consistent with Heinz body hemolysis related to phenazopyridine (Figure 1B). At this point, the patient had been utilizing phenazopyridine at a dose of 200 mg PO TID for 43 days consecutively (cumulative dose 28g) and was thus discontinued.
Ten days later (post-HCT day 44), a repeat peripheral blood smear showed minimal residual morphologic evidence of Heinz body hemolysis. Ursodiol was discontinued, hemoglobin improved to 10.1 g/dL, total bilirubin was normal at 1.1 mg/dL, absolute reticulocyte count decreased to 175.2 x109/L and lactate dehydrogenase decreased to 256 U/L. On last review, the patient continues to do well and has not required further red blood cell transfusions. Table 1 and Figure 2 summarizes the patient’s course and lab findings.