MRD response in two patients with AML treated with oral maintenance therapy

Case 1: A patient with CR on oral azacitidine

Presentation and investigation

A 63-year-old male presented with symptomatic anaemia (haemoglobin [Hb], 2.9 g/dL) and loss of appetite in October 2022. He was an ex-smoker, and had a history of hypertension and hyperlipidaemia, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0.

Complete blood count (CBC) showed an elevated white blood cell (WBC) count of 92.7 x 10⁹/L and a decreased platelet count of 11 x 10⁹/L. Flow cytometry detected 10 percent myeloid blasts. Genetic test revealed t(8;21) translocation and loss of the Y-chromosome (-Y) while next-generation sequencing (NGS) detected ASXL1, KIT, NRAS and CREBBP mutations, leading to a diagnosis of acute myeloid leukaemia (AML) with favourable cytogenetic risk.

Treatment and response

The patient was treated with induction chemotherapy with the 7+3 regimen (7 days of cytarabine and 3 days of daunorubicin) and gemtuzumab. This treatment was complicated by neutropenic sepsis, but the patient eventually recovered. His post-induction measurable residual disease (MRD) status was positive.

Between December 2022 and January 2023, the patient was started on two courses of high-dose cytarabine with gemtuzumab as consolidation therapy. However, he experienced another episode of neutropenic sepsis following the 2^nd consolidation therapy, which led to intensive care unit (ICU) admission. Therefore, no further consolidation chemotherapy was provided. He achieved complete remission (CR), but his MRD status remained positive at 0.3 percent in February 2024. (Figure 1)

Considering his cytogenetic risk status, age, comorbidities and adverse events (AEs) from consolidation chemotherapy, haematopoietic stem-cell transplantation (HSCT) was not provided. In April 2023, the patient was started on maintenance therapy with oral azacitidine 300 mg QD for 14 days per 28-day cycle. After 2 months, he became MRD negative. (Figure 1)

Prophylactic antiemetics were prescribed. However, the patient chose not to take the antiemetics as he experienced only mild gastrointestinal AEs, including mild nausea and vomiting in the first few cycles.

As of October 2024, the patient had been on oral azacitidine 300 mg QD for 1.5 years. He remained MRD-negative and symptom-free with a normal blood count.

Case 2: A patient with CRi on oral azacitidine

Presentation and investigation

A 60-year-old female with a medical history of diabetes, hypertension, dyslipidaemia, knee osteoarthritis, and a cardiac shunt presented with anaemia (Hb, 7.8 g/dL) in July 2022. CBC and flow cytometry showed a WBC count of 61 x 10⁹/L, a platelet count of 22 x 10⁹/L, and 39 percent myeloid blasts. NGS did not detect any variants. Bone marrow biopsy confirmed a diagnosis of AML with t(8;21) translocation.

Treatment and response

The patient received induction chemotherapy with the 7+3 regimen (7 days of cytarabine and 3 days of daunorubicin) plus gemtuzumab in August 2022. However, she developed Escherichia coli septicaemia but eventually recovered. Follow-up assessment showed CR and positive MRD status.

Two courses of high-dose cytarabine with gemtuzumab as consolidation therapy were provided in September–October 2022. However, the patient was unable to continue further chemotherapy as she developed Klebsiella septicaemia and pneumonia after the first round of consolidation chemotherapy and infection of the central venous catheter after the second round of consolidation chemotherapy.

She achieved CR with incomplete blood count recovery (CRi; platelet count, 16–24 x 10⁹/L), but her MRD status was positive. Her MRD status was positive at 0.029 percent in March 2023. (Figure 1)

The patient did not undergo HSCT due to her risk profile, comorbidities, and AEs from intensive chemotherapy treatment. Oral azacitidine 300 mg QD for 14 days per 28-day cycle was initiated in May 2023 after her platelet count reached 50 x 10⁹/L. She became MRD-negative after 1 month of oral azacitidine treatment. (Figure 1) As her platelet counts dropped to <50 x 10⁹/L during treatment, azacitidine dosage was withheld, and subsequently reduced to 200 mg QD for 14 days, further reduced to 200 mg QD for 7 days in December 2023. (Figure 2) she experienced grade 1–2 nausea, which resolved with prophylactic antiemetics subsequently.

As of August 2024, the patient had been on oral azacitidine for >1 year and remained symptom-free and MRD negative. Her latest platelet count was 71–95 x 10⁹/L.

Discussion

As demonstrated in both cases, intensive chemotherapy can lead to high CR rates in newly diagnosed AML.^1,2 However, these remissions are often transient. Most patients (80–90 percent) eventually have a relapse.¹ While HSCT is potentially curative, many patients, including the two patients above, are ineligible for HSCT.^3,4 Some patients referred for HSCT still cannot proceed with it due to prohibitive comorbidity.^4,5 Additionally, HSCT is associated with significant toxicities and occasionally fatal complications, such as infections and graft-versus-host disease.⁶

Effective maintenance therapies that can reduce the risk of relapse and prolong overall survival (OS) are needed for patients who are not candidates for HSCT, such as our two patients described above.^1,4 In the National Comprehensive Cancer Network (NCCN) guidelines, oral azacitidine is the only treatment with a category 1 recommendation for non–core binding factor (CBF) AML patients who are unable to complete intensive curative therapy after first CR following intensive induction chemotherapy.⁷

The phase III QUAZAR AML-001 trial showed significant long-term OS (3-year OS rates, 37.4 vs 27.9 percent; 95 percent confidence interval [CI], 0.9–18.1) and relapse-free survival (RFS; median, 10.2 vs 4.8 months; p<0.001) benefits with oral azacitidine vs placebo.^1,8 Oral azacitidine improved OS and RFS regardless of NPM1 and FLT3 mutation status at diagnosis, cytogenetic risk, or post–intensive chemotherapy MRD status.⁹

Notably, oral azacitidine treatment extended the duration of MRD negativity by 6 months vs placebo and resulted in a higher conversion rate from MRD positivity at baseline to MRD negativity during treatment (37 vs 19 percent; odds ratio, 2.50; 95 percent CI, 1.35–4.61). Most MRD responses (76 percent) occurred ≤6 months from randomization, which is consistent with the experience of both of our patients who achieved MRD negativity within 2 months after oral azacitidine treatment initiation.¹⁰ (Figure 1)

Detectable MRD while in CR is associated with higher relapse risk and shorter survival.¹¹ Both of our HSCT-ineligible patients remained relapse-free for >1 year after achieving MRD negativity with oral azacitidine. Their experience together with clinical trial data suggested that oral azacitidine treatment should be an option for patients who cannot complete intensive curative therapy, especially those who are MRD-positive following intensive chemotherapy.

Gastrointestinal events are the most common AEs associated with oral azacitidine, but these are typically low-grade and tend to occur during the first few treatment cycles. Antiemetic prophylaxis during at least the first two cycles and as-needed symptomatic intervention may facilitate treatment compliance.^12,13

It is advised to monitor CBC for the first two cycles and prior to the start of each cycle of oral azacitidine thereafter. Additionally, following any dose reduction due to myelosuppression, monitoring should be increased to every other week for the next two cycles. Patient 2 experienced thrombocytopenia, which is a common AE of oral azacitidine (all grade, 33 percent; grade 3–4, 22 percent).^1,12 In clinical practice, patients’ platelet count typically decreases by 20–30 percent during mid-cycles and generally returns to baseline levels before the subsequent dose. As demonstrated in case 2, treatment should be interrupted until platelet count recovery and then resumed at a reduced dosage if patients develop thrombocytopenia (platelets <50 × 10⁹/L with bleeding) in two consecutive cycles.¹²

In summary, the decision on whether to offer HSCT is complex and involves consideration of patients’ fitness, risk of AML relapse, and availability of donors.¹⁴ In AML, even after undergoing intensive chemotherapy, the risk of relapse is high, particularly for patients who remain MRD-positive after induction and consolidation therapies.^1,11 Oral azacitidine serves as a maintenance therapy for these HSCT-ineligible patients, leading to improved OS and RFS.^1,12 It may also facilitate MRD conversion from positive to negative status and extend the duration of MRD negativity.¹⁰ Importantly, post-remission maintenance therapy that prolongs MRD negativity or converts MRD-positive patients to MRD-negative may delay or prevent relapse and improve OS.¹⁰

References: 

1. N Engl J Med 2020;383:2526-2537. 
2. Oncol Res 2021;28:811-814.
3. Stem Cells 2012;30:1581-1586.
4. Transplant Cell Ther 2023;29:460.e1-460.e9.
5. Blood 2005;106:2912-2919.
6. Bone Marrow Transplant 2020;55:126-136. 
7. NCCN Guidelines. Acute Myeloid Leukemia, version 3.2024.
8. Am J Hematol 2023;98:E84-E87.
9. Blood 2022;140:1674-1685.
10. Blood 2022;139:2145-2155.
11. J Hematol Oncol 2021;14:137.
12. Onureg Hong Kong Prescribing Information, July 2023. 
13. J Hematol Oncol 2021;14:133. 
14. J Clin Med 2020;9:554.