AML And The High Risk Of Multiple Infectious Complications

Dr Porpon Rotjanapan

Attending Physician
Faculty of Medicine Ramathibodi Hospital
Mahidol University
Bangkok, Thailand

Background and diagnosis

A 54-year-old man presented with complaints of low-grade fever and malaise that persisted for 2 weeks. Evaluation of his medical history did not reveal any significant medical conditions. Initial investigations into the patient’s complete blood count detected elevated total white blood cell (WBC) count of 120,000 cells/μL with 80% blast cells. These findings led to a diagnosis of acute myelogenous leukemia (AML).

Management

The patient was started on a chemotherapy regimen consisting of cytarabine and idarubicin. Immediately following the first course, the patient’s fever began to trend downwards.

This changed on Day 3 of the treatment cycle, when the patient’s temperature spiked to 39.2°C. He also developed small, shallow oral ulcers, which tested negative for cytomegalovirus (CMV) and for herpes simplex virus (HSV) by polymerase chain reaction (PCR). The patient was then prescribed cefepime for neutropenic fever.

On Day 5, the patient developed diarrhea, losing around 750 mL per day. A stool examination did not detect the presence of red blood cells, WBC or pathogens like bacteria or fungi. A PCR test further confirmed that there was no Clostridium difficile present in the stool samples. However, blood cultures detected Enterococcus faecium. His antibiotic regimen was subsequently switched to empirical treatment with imipenem and vancomycin.

However, his temperature continued to peak on Day 9 postchemotherapy, reaching 40.2°C, while his symptoms of diarrhea worsened, with a daily stool volume of 2,000 mL. The blood culture test was repeated, after which the patient had fluconazole added to treatment.

The patient’s high fever and symptoms of diarrhea persisted on Day 11. Results of the blood culture test showed budding of yeasts, identified as Candida tropicalis. Antifungal treatment was subsequently switched from fluconazole to anidulafungin.

By Day 16 of the treatment cycle, the patient’s diarrhea had improved slightly. However, the fever persisted within the range of 39.0 to 40.0°C. A computed tomography (CT) scan of his chest and abdominal regions detected diffuse thickening of small bowel and ascending colon wall, although there were no signs of lung parenchymal abnormalities. Another blood culture was scheduled.

He became hypotensive on Day 17, with systolic blood pressure levels dropping to the 70’s mmHg range. The blood culture test reported the growth of gram-negative bacteria, later identified as Acinetobacter baumannii. Given the high rates of multidrug resistance associated with the bacteria, colistin was added to treatment.

The patient’s final anti-infectious treatment regimen for the infections was adjusted to include: imipenem, amikacin, daptomycin, ganciclovir, anidulafungin, intravenous immunoglobulin and granulocyte-colony stimulating factor. The patient’s fever finally subsided on Day 22 post-chemotherapy and he was discharged 5 days later.

This case illustrates the morbidity associated with candidemia in patients who receive remission induction therapy for AML. Clearly this patient only received antibacterial coverage in the beginning of the treatment course for a concern of high likelihood of gastrointestinal bacterial translocation causing infectious complications. However, considering data on microbiota in the gastrointestinal tract, the human body harbors not only bacteria, but fungi, particularly Candida spp., which are prominent residents.¹ This potentially indicates that gut bacteria as well as fungi are able to cause severe infections especially in this setting.

A large number of randomized controlled trials have been performed and the data as a whole indicate that antifungal prophylaxis does reduce the incidence and mortality of IFI in patients with chemotherapy-induced neutropenia. For example, in a meta-analysis in cancer patients who received chemotherapy for hematologic malignancies or underwent hematopoietic stemcell transplantation, antifungal prophylaxis reduced all-cause mortality.² However, when 24 studies that included only patients with acute leukemia where analyzed, the reduction in mortality was only borderline significant (relative risk 0.88, 95% confidence interval 0.74 to 1.06).² In terms of prophylaxis treatment choice, fluconazole reduced 30-day mortality significantly but not end-of-follow-up mortality. Prophylaxis with itraconazole did not reduce all-cause mortality. Another meta-analysis in neutropenic patients with hematologic malignancies showed that prophylaxis with itraconazole cyclodextrine solution (syrup), but not itraconazole capsules, was associated with a reduction in the incidence of IFIs and the associated mortality.³

Managing risk of infections in AML: Key points

• AML patients are at risk of bacterial and fungal infections due to their compromised immune systems; these infections are major causes of morbidity and mortality in neutropenic patients.⁴

• Prophylactic antifungal and antibiotic therapies are key to preventing bacterial and fungal infections.⁴

• A review of randomized AML trials concluded that antifungal prophylaxis reduced fungal infection-related mortality and IFIs.²

• Consider local infectious trends and drug-resistance patterns before prescribing prophylactic anti-infectious treatment.⁴

References:

1. Pérez JC, Johnson AD. PLoS Pathogens 2013;9:e1003780.
2. Robenshtok E, et al. J Clin Oncol 2007;25:5471-5489.
3. Glasmacher A, et al. J Clin Oncol 2003;21:4615-4626.
4. Döhner H, et al. Blood 2010;115:453-474.