Lethal small bowel necrosis due to aspergillosis during acute promyelocytic leukemia induction

A 45-year-old female presented with persistent headache and generalized bruising. A complete blood count (CBC) showed mild anemia (11.5 g dL−1), thrombocytopenia (15 × 109/L), leukocytosis (43 × 109/L) with promyelocyte predominance (38.3 × 109/L), and a coagulopathy with INR 1.93, D-dimer > 20 μg mL−1 fibrinogen-equivalent units (FEU) (0.0–0.50 μg mL−1 FEU), and fibrinogen 150 mg dL−1 (200–420 mg dL−1). Peripheral blood and marrow aspirate smears demonstrated atypical promyelocytes with hypogranulation and multiple Auer rods (Fig. 1A). Myeloperoxidase cytochemical stain performed on the peripheral blood showed the atypical cells to be of myeloid origin (Fig. 1B). Bone marrow biopsy and aspiration showed cellularity of nearly 100% that was diffusely and extensively effaced by leukemic promyelocytes (Fig. 1C, D). Flow cytometry showed blasts expressing CD13, CD33, partial CD34, CD45, partial CD117, and partial cytoplasmic myeloperoxidase, consistent with a clonal myeloid neoplasm. Florescent in situ hybridization (FISH) analysis indicated that 95.5% of interphase cells demonstrated promyelocyte leukemia/retinoic acid receptor alpha (PML-RARA) fusion gene. G-banding karyotyping was reported as 46,XX,t(15;17)(q24.1;q21)[18]/46,XX[2]. Figure 1 Blood and bone marrow samples from patient at diagnosis. A: Diagnostic peripheral smear with leukemic promyelocytes with multiple Auer rods (left) and bilobed hypogranulated forms (Wright-Giemsa ×100 oil). B: Leukemic promyelocytes (right) staining ... The patient had high risk acute promyelocytic leukemia (APL), which is characterized by the morphologic predominance of leukemic promyelocytes and a t(15;17)(q22;q12) involving the retinoic acid receptor alpha gene. High-risk APL is characterized by a white blood cell count (WBC) at presentation of >10 × 109/L and is associated with a high risk of death during induction therapy and relapse. Vitamin A derivative all-trans retinoic acid (ATRA) is mainstay of APL treatment and APL today is considered to be the most curable subtype of all AMLs. The patient was started on all-trans retinoic acid (ATRA) 45 mg m−2, idarubicin 12 mg m−2 Days 1–4, and dexamethasone 10 mg IV every 6 hr for high risk acute promyelocytic leukemia (APL). Supportive care was provided for the patient’s coagulopathy with fresh frozen plasma, cryoprecipitate and platelet transfusions. Prophylactic antimicrobial therapy was initiated with acyclovir, levofloxacin, and fluconazole. On Day 6 of induction chemotherapy (D+6), the patient was noted to have developed peripheral edema and significant weight gain. Baseline radiograph of the chest demonstrated pleural effusions. These findings were thought due to mild ATRA or differentiation syndrome, which is generally characterized by fever and respiratory distress. However, it is also associated with weight gain, lower extremity edema, pleural or pericardial effusions, and episodic hypotension. The patient continued treatment with dexamethasone. On D+10, she developed neutropenic fever, with isolation of methicillin-resistant Staphylococcus aureus (MRSA) in blood cultures. Intravenous vancomycin and ceftazidime were started with resolution of her fever. The patient again became febrile on D+19. Chest-computed tomography (CT) showed bilateral small pleural effusions in the setting of a steroid taper. ATRA was discontinued due to concern for worsening ATRA syndrome and steroids were resumed. On this day, the patient developed abdominal distention and emesis. Abdominal CT demonstrated small bowel obstruction, thought to be secondary to ischemia, which was managed conservatively in the setting of her ongoing neutropenia and clinical stability. The patient’s antibiotic regimen was adjusted to metronidazole and piperacillin/tazobactam. Intravenous voriconazole replaced fluconazole on D+26. Additionally, she was started on granulocyte colony-stimulating factor. During this time, she noted double vision and color distortion. A head CT was unremarkable and brain magnetic resonance imaging (MRI) was delayed secondary to increased respiratory distress, which the patient developed in the setting of continued abdominal distention. She was intubated and repeat abdominal CT imaging showed a proximal closed loop small bowel obstruction (Fig. 2). Figure 2 Coronal reconstruction image of a contrast enhanced abdomen-pelvis CT demonstrates small bowel obstruction and ascites (*). The arrow points to the transition point. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] ... Exploratory laparotomy was performed, with resection of a portion of proximal small bowel. At the time of surgery, the proximal jejunum was grossly necrotic. Small bowel pathology on D+32 showed transmural necrosis, with numerous invasive septated fungal organisms consistent with Aspergillus species and extensive angioinvasion by these organisms (Fig. 3A–D). Aspergillus galactomannan testing of serum was negative on D+32. Figure 3 Histopathological analysis of bowel resection specimen. A–D: Duodenal resection specimen. A: Extensive necrosis, ulceration with residual mucosa (hematoxylin and eosin ×10). B: Angioinvasion by fungal forms (hematoxylin and eosin ×40). ... Bone marrow biopsy on D+33 showed that she was in hematologic CR, and FISH was negative for PML-RARA fusion gene. ATRA was restarted. Possible seizure activity was noted, and a lumbar puncture (LP) and brain MRI were performed. MRI showed subarachnoid hemorrhage in the right occipital and parietal lobes. LP opening pressure was 38 cm H2O, with fluid analysis consistent with hemorrhage, glucose of 53 mg dL−1, and protein of 246 mg dL−1. The patient remained on vancomycin, piperacilin-tazobactam, and voriconazole. Serum and cerebrospinal fluid (CSF) galactomannan antigen by enzyme-linked immunoassay were both negative. On D+37, bronchoscopy showed clear airways without alveolar hemorrhage. Bronchoalveolar lavage cultures and cytology revealed no evidence of mold organisms. Candida glabrata was isolated in culture and was shown to be resistant to all tested azole drugs. Transesophageal echocardiogram was unremarkable for vegetation or shunt. ATRA was discontinued. The patient’s course was further complicated by ventilator dependence, abdominal abscess requiring drainage, continued transfusions for ongoing coagulopathy, oliguria, and probable sepsis while on antibacterial antimicrobial therapy. On D+45, an esophagogastroduodenoscopy showed a large bleeding duodenal vascular mass. On D+51, a gastrointestinal (GI) tract perforation was suspected when nasogastric tube feeds began draining through the patient’s abdominal abscess drain. A CT of the abdomen and pelvis showed a phlegmon in the left hemiabdomen containing small bowel loops and hematoma in the right hemiabdomen (Fig. 4A) as well as small bowel loops with wall thickening (Fig. 4B). Exploratory laparotomy was remarkable for necrotic bowel involving multiple loops of small bowel with transmural necrosis and perforation. The patient was transitioned to comfort cares and died on D+52. Figure 4 A: Coronal reconstructed image of a contrast enhanced abdomen and pelvis CT demonstrates a phlegmon (arrow) in the left hemiabdomen containing small bowel loops and layering blood products. Hematoma (*) in the right hemiabdomen. B: Axial images demonstrate ... Limited postmortem exam without central nervous system (CNS) examination was performed. Hemorrhagic necrosis of the distal duodenum and proximal jejunum without perforation was found, but no convincing invasive fungal organisms consistent with Aspergillus species were identified at autopsy despite very liberal tissue sampling for histopathology. The lungs were remarkable only for mild pulmonary edema and congestion. No convincing leukemic promyelocytes were seen at autopsy; however, our evaluation was limited due to the fact that granulocytes have autolytic changes at autopsy.