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.