Intensified-Dose Chemotherapy in Combination With Gemtuzumab-Ozogamicin for the Treatment of Favorable-Risk Acute Myeloid Leukemia (AML)

Chemotherapy has been the standard of treatment for acute myeloid leukemia (AML). With the emergence of new therapies for AML like gemtuzumab-ozogamicin and FLT3 inhibitors, such as sorafenib, midostaurin, and gilteritinib, the optimal dose of chemotherapy and safety profile in different age groups when combined with these new therapies is yet to be established. There are limited data on the treatment of AML by combining intensified daunorubicin (doses of 90 mg/m2) with gemtuzumab-ozogamicin (GO). We report a young adult with favorable-risk AML treated with daunorubicin at a dose of 90 mg/m2 combined with GO, who had a complete response after induction but had a profound nadir of platelet count after induction and consolidation.


Introduction
Chemotherapy has been the backbone of the treatment of acute myeloid leukemia (AML). Targeted treatment (FLT3 inhibitors and isocitrate dehydrogenases (IDH) inhibitors) and others (i.e. venetoclax) are now approved for AML treatment. The safe and optimal combination of these new therapeutic agents with standard chemotherapy remains a key question, particularly if intensification of the backbone chemotherapy regimen is still relevant. Some clinical trials reported the benefits of intensified daunorubicin when compared to the standard dose in combination with FLT3 inhibitors. Gemtuzumab-ozogamicin (GO), an anti-CD33 monoclonal antibody linked to a DNA-damaging cytotoxic drug, was developed after the discovery that anti-CD33 antibodies bind selectively to AML cells and are internalized across the tissue membrane. A retrospective study published by Singh A et al. demonstrated the safety of intensified daunorubicin and GO and the combination with FLT3 inhibitors in patients with favorable-risk AML [1]. The optimal chemotherapy combination with these new agents for the management of young AML patients remains unclear.

Case Presentation
A 50-year-old woman with recurrent headaches was found to have leukocytosis at an outside hospital and was transferred to our hospital. Her past medical history was significant for celiac disease, emphysema, arthritis, fibromyalgia, and chronic regional pain syndrome. Her home medications include bronchodilators and pain medications. The patient denied any history of malignancy in her family. She was tachypneic and hypoxic and required oxygen supplementation on arrival. Labs were notable for a white blood cell count of 38.2 k/mm 3 with 72% blasts with monocytic differentiation, hemoglobin 10.2 gm/dl, platelet count 113 k/mm 3 , fibrinogen >600 mg/dL, lactate dehydrogenase 604 U/L, and uric acid 4.8 mg/dL. Bone marrow biopsy and aspiration with flow cytometry revealed 89% myeloid blasts and findings consistent with acute myeloid leukemia (AML) non-M3 phenotype. Given her acute presentation, we elected to begin induction shortly after preliminary pathology results. She was treated with cytarabine 200 mg/m 2 and intensified daunorubicin 90 mg/m² per day for three days (7+3 regimen) for induction. The results of the next-generation sequencing (NGS) panel for AML came a week later. NPM1 was detected and other mutations, including FLT3, were negative. No other cytogenetic abnormalities were detected. Based on data supporting the use of gemtuzumab-ozogamicin (GO) in favorable-risk AML [2], we added GO for Day 7 and Day D10. Her induction course was complicated by thrombocytopenia with platelet count <50 k/mm 3 for four weeks and reached a nadir of 1 k/mm 3 .
The platelet count was <10 k/mm 3 for 11 days post-induction. Other complications post-induction were neutropenic fever, bacteremia with vancomycin-resistant Enterococcus, Staphylococcus epidermidis, colitis, and a rectal abscess, which required surgical drainage. The patient was in complete remission after induction and has had three cycles of consolidation thus far with high-dose cytarabine (3 g/m 2 ) and GO. Pathology from bone marrow revealed complete remission with no more NPM1 or other mutations. of the daunorubicin cohorts and used a higher threshold of 100 k/mm 3 platelets to constitute recovery. Our patient's platelet recovery was 28 days (>100 k/mm 3 ) after induction. However, our patient had a profound nadir of platelet count with < 10 k/mm 3 for 11 days. She had a similar nadir period after her first consolidation cycle requiring transfusions. She has been noted to have human leukocyte antigen (HLA) antibodies, which have contributed to the thrombocytopenia picture and her response to transfusions. Nonetheless, further attention should be paid to the toxicity of thrombocytopenia in the context of adding GO to higher doses of daunorubicin.

Conclusions
In the real-world setting, when NGS results may not be immediately available and there is an urgency to treat, one would need to consider starting 90 mg/m² of daunorubicin and then adding GO in young patients with AML who have favorable risk features. Randomized controlled trials with a large sample size need to be done comparing the intensified vs standard doses of daunorubicin when combined with GO to determine the optimal dose and safety profile.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.