Maintenance Therapy of a Female Patient with AML After Intense Chemotherapy – Case Study
The following case study presents the case of a female patient with acute myeloid leukemia (AML) who experienced life-threatening complications after the second consolidation chemotherapy, rendering her incapable of undergoing further intense therapy or allogeneic HSCT. In this situation, maintenance therapy with oral azacitidine proved beneficial – this modality, due to its good tolerance, can be used as a bridge until allo-HSCT can be performed in patients in poor clinical condition.
Introduction
Acute myeloid leukemia is a malignant disease of the hematopoietic system characterized by the accumulation of abnormal immature myeloid cells (blasts) in the bone marrow, leading to the suppression of physiological blood element production. It predominantly affects older patients, with incidence increasing with age.1 It is an aggressive disease, and without specific therapy, it can be fatal in a short time.
The current classification is based on molecular genetic and cytogenetic abnormalities, which are associated with different prognoses and clinical courses of the disease. Choosing the appropriate therapy depends on the characteristics of the disease itself, but evaluating the overall condition and comorbidities of the patient is equally important. Intensive remission induction chemotherapy followed by 2–3 cycles of consolidation chemotherapy and/or allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the foundation of curative treatment.2
Despite improvements in supportive care over the last decades, the high risk of numerous life-threatening complications, especially in older and polymorbid patients, remains a significant issue.
Case Description
A 54-year-old female patient was referred for hospitalization in August 2022 from a district hematology clinic to our center due to suspected acute leukemia. The patient was originally seen during a scheduled check-up with her general practitioner prior to a planned colonoscopy for a positive occult blood test in the stool. Due to the detection of leukocytosis and anemia, she was referred to the hematology clinic. Additionally, she experienced a 2-week history of an irritating cough and sore throat, for which her general practitioner prescribed empirical antibiotic therapy, resulting in only slight improvement, and newly swollen gums. She reported no fever or chills and denied any bleeding symptoms. The patient had been treated for hypertension and hypercholesterolemia, was obese, and was on medication only for an antihypertensive and a statin. She worked as a nurse's aide in urology.
Upon admission to our clinic, her blood count showed dominant leukocytosis with monocytosis and 13% undifferentiated blasts, anemia, and a normal platelet count (leukocytes 65 × 109/l, hemoglobin 87 g/l, platelets 218 × 109/l). On the second day after admission, a sternal puncture was performed, closing the diagnosis as AML otherwise unspecified, myelomonocytic. Molecular genetic testing revealed the presence of NPM1 and FLT3-TKD mutations, cytogenetic testing showed no abnormalities – medium risk, overall risk assessed as low according to the 2017 ELN (European LeukemiaNet) criteria.
Cytoreduction with hydroxyurea was initiated, and screening for infectious foci, including colonoscopy, was performed, with findings of diverticulitis and a polyp that was excised. After the leukocytosis decreased, standard induction chemotherapy "3+7" (anthracycline + cytarabine) + midostaurin for FLT3 positivity, without gemtuzumab ozogamicin due to concerns about a higher risk of complications stemming from older age, obesity, hepatopathy, and diverticulitis. Complete remission with incomplete blood count improvement was achieved after induction therapy, with a high load of NPM1 mutation persisting. The first consolidation therapy was administered in a HiDAC (high-dose cytarabine) + midostaurin regimen as post-remission therapy. The neutropenia period was complicated by febrile neutropenia and COVID-19 infection with a mild course, achieving overall disease remission with persistent molecular positivity of minimal residual disease (MRD). Subsequently, as part of the first-line treatment, it was decided to continue consolidation in the same regimen and then to perform allo-HSCT from an unrelated 10/10 donor.
In December 2022, on the 19th day of the second consolidation therapy, the patient was acutely admitted to our clinic for febrile neutropenia therapy. Laboratory tests showed severe pancytopenia (leukocytes 0.08 × 109/l, hemoglobin 73 g/l, platelets 11 × 109/l) and initially mild CRP elevation (61 mg/l). Empirical antibiotic therapy and hydration were initiated; however, on the second day, the patient developed septic shock with multi-organ failure. She was transferred to the intensive care unit, where she required circulatory support up to three vasopressors, and a step-up antimicrobial therapy was started. Anuria and acute renal failure developed, and she was connected to continuous hemodialysis. ESBL Klebsiella pneumoniae was isolated from blood cultures, and antibiotics were adjusted accordingly. There was persistent hemodynamic instability, global hypokinesia of the heart with a left ventricular ejection fraction (EF) of 30-35% as seen on echocardiography. Due to the continued severe clinical condition, granulocyte colony-stimulating factor (G-CSF) support was started, but it was ineffective, with persistent profound neutropenia; therefore, donor granulocytes were administered, which led to an increase in leukocytes. CRP levels gradually decreased, diuresis resumed, continuous dialysis was switched to intermittent, and the polyuric phase of renal failure developed, continuing massive hydration and ion substitution. The further course was complicated by the development of herpetic stomatitis and clostridial colitis. Over the following weeks, there was a gradual improvement in the clinical condition, physical rehabilitation began, renal parameters improved, and blood count recovery was gradually evident. After eight weeks of hospitalization, the patient was discharged to outpatient care.
After the second consolidation, persistent overall hematological remission with molecular MRD positivity of NPM1 (78.4 copies) and FLT3-TKD (0.02%), laboratory persistent mild renal insufficiency, continued ion substitution, blood count recovery, and ongoing intensive rehabilitation, the patient was walking with a walker at home. Due to the overall condition and life-threatening complications after the second consolidation chemotherapy, the patient was unable to undergo further intense therapy or allo-HSCT. Therefore, maintenance therapy with oral azacitidine at a standard dose of 300 mg once daily for 14 days in each 28-day cycle was initiated. After the first cycle of this therapy, overall hematological remission with molecular MRD negativity was achieved, followed by full normalization of renal parameters and improvement in the overall condition of the patient. The therapy was also very well tolerated, requiring only concomitant antiemetic therapy, without hematological toxicity or any infectious complications. After the 8th cycle of azacitidine, the patient returned to normal life and even resumed her original job at the hospital.
After the 13th cycle of therapy in April 2024, newly borderline molecular MRD positivity of NPM1 was detected, and a subsequent bone marrow sample unfortunately confirmed a molecular relapse of the disease. Due to the excellent clinical condition of the patient, it was decided to proceed with allo-HSCT from an unrelated donor, which is planned for May 2024.
Conclusion
Oral azacitidine is a newly available form of maintenance therapy indicated for patients with AML with moderate or unfavorable cytogenetic risk who achieved overall hematological remission after intense first-line chemotherapy and are not eligible for allo-HSCT.
The effect of oral azacitidine in terms of significantly improving overall survival and relapse-free survival without worsening the quality of life of patients was clearly demonstrated in the randomized QUAZAR AML-001 study.3 Due to its good tolerance, azacitidine can also be used as a bridging therapy to perform allo-HSCT in patients in poor clinical condition after severe complications during intense first-line therapy.
MUDr. Natália Podstavková
Internal Hematology and Oncology Clinic, Faculty of Medicine, Masaryk University and University Hospital Brno
References:
1. De Kouchkovsky I., Abdul-Hay M. Acute myeloid leukemia: a comprehensive review and 2016 update. Blood Cancer J 2016; 6(7): e441, doi: 10.1038/bcj.2016.50.
2. Döhner H., Wei A. H., Appelbaum F. R. et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 2022; 140 (12): 1345–1377, doi: 10.1182/blood.2022016867.
3. Wei A. H., Döhner H., Sayar H. et al. Long-term survival with oral azacitidine for patients with acute myeloid leukemia in first remission after chemotherapy: updated results from the randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial. Am J Hematol 2023; 98 (4): E84–E87, doi: 10.1002/ajh.26847.
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2011-CZ-2400009
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