A Century of Hypomethylating Agent: A Remarkable Response to Azacitidine Monotherapy for Relapsed Acute Myeloid Leukemia – A Case Report Open Access

Introduction: Acute myeloid leukemia (AML) is a disease of the elderly with a median age at diagnosis of 68 and with a very poor prognosis outside of those patients who have cytogenetic and/or molecular findings which confer a better prognosis. Most fit patients are treated with chemotherapy and then allogeneic hematopoietic stem cell transplant if they are intermediate or poor risk by ELN 2022 criteria (aSCT). aSCT is the mainstay of curative treatment although many patients are not candidates due to age, performance status, and comorbidities. In patients who are not candidates for curative treatment, low-intensity chemotherapy regimens, including monotherapy with hypomethylating agents (HMAs) such as azacitidine or decitabine, may be trialed with a palliative intent. In patients who have relapsed disease, responses to therapy are generally dismal and overall survival is extremely low. Case Presentation: We report a 73-year-old male patient who was initially diagnosed with inversion 16 AML, underwent induction chemotherapy with 7 + 3 and then consolidation with 4 cycles of high-dose cytarabine. He was found to have relapse after consolidation but did not elect to undergo allogeneic bone marrow transplant and so was given palliative single-agent azacitidine. He has since received over 100 cycles of azacitidine and remains in remission. Conclusion: To our knowledge, no other reports describe relapsed AML treated with HMA monotherapy achieving such exceptional survival. The remarkable response duration suggests mechanisms beyond cytotoxicity. Further research should explore HMA monotherapy’s effects across AML subgroups, including inv(16).

Acute myeloid leukemia (AML) is the most common form of acute leukemia with a median age of diagnosis of 68 years [1]. It is a heterogenous disease that comprises a wide range of molecular and cytogenetic variations that lead to extremely variable presentations, making treatment very nuanced [2]. Despite recent improvement in therapy, prognosis for patients with AML remains poor with a 5-year overall survival (OS) of 31.7% [3]. Curative treatment for AML consists of induction chemotherapy followed by allogeneic stem cell transplantation (aSCT), consolidation chemotherapy, or both [4]. Often, because of age and comorbidities, patients are unable to tolerate curative treatment [5]. A subset of these patients elects to pursue some form of palliative chemotherapy. In this report, we describe a unique case of a patient with AML who relapsed after completing induction and consolidation chemotherapy and elected to not pursue aSCT. Notably, he had inv(16) which is associated with a relatively high rate of complete remission (CR) and OS [6, 7]. The patient was initiated on palliative azacitidine in 2012 and, remarkably, is still alive and recently completed his 100th cycle of therapy.

A 73-year-old male with a past medical history of hypercholesterolemia and chronic sinusitis presented to his primary care physician with fatigue, dyspnea on exertion, and fever. Bloodwork was ordered and he was found to be pancytopenic. He underwent a bone marrow biopsy on January 7th, 2011, that showed a myeloblast population constituting 11% of all cells. These cells were CD13+, CD15+, CD33+, CD34+, CD38+, CD117+, MPO+, and HLA-DR+. Karyotype studies showed inv(16) with CBFB:MYH11 gene fusion on FISH probe analysis. Based on the finding of inv(16) which does not have a minimum blast requirement, he was diagnosed with AML. He then underwent treatment with (7 + 3) idarubicin/cytarabine starting on January 14, 2011. His course was complicated by neutropenic fever and Pseudomonas bacteremia for which he was treated with antibiotics. Repeat bone marrow biopsy was conducted on February 14, 2011, which showed a mildly hypercellular marrow with myeloid hyperplasia but was negative for residual leukemia. No abnormal cell population was detected on flow cytometry. Cytogenetic studies confirmed no rearrangements including inv(16). Subsequently, he completed 4 cycles of consolidative high-dose cytarabine (HIDAC) and was not planned for aSCT due to relatively high rates of cure after chemotherapy alone. His consolidation phase of chemotherapy was complicated by pancytopenia and neutropenic fever. Several months after completion of HIDAC, his peripheral blood counts began to fall and a bone marrow biopsy performed on March 12, 2012, showed a myeloblast population constituting 3% of all cells. These cells were CD10−, CD13+, CD14−, CD15−, CD33−, CD34+, CD38+, CD56−, CD64−, CD117+, and HLA-DR+. Cytogenetic studies again showed inv(16). These findings were consistent with recurrent disease. Treatment options were discussed with the patient including aSCT and palliative chemotherapy with azacitidine or decitabine. The patient decided to pursue palliative treatment with azacitidine and started treatment on May 1, 2012. Of note, this was prior to the wide usage of venetoclax as synergistic therapy with hypomethylating agents. Within the first two cycles of azacitidine treatment, he was noted to have improving performance status and gradually required less frequent blood and platelet transfusions. As a result of his normalized blood counts and his desire not to pursue aggressive therapy, a repeat bone marrow biopsy was never completed, but his blood counts have remained stable over the past 12 years. Prior to azacitidine therapy, on April 30, 2012, he had a white blood cell count of 1,500/μL, hemoglobin of 9.4 g/dL, and platelets of 31,000/μL. His CBC on October 2, 2023, showed a white blood cell count of 4,600/μL, hemoglobin of 13.2 g/dL, and platelets of 101,000/μL. He has continued to tolerate the drug well and completed cycle 100 of azacitidine on August 27, 2023, marking a century of HMA. Of note, repeat cytogenetics or FISH analysis was not performed since starting azacitidine.

Induction chemotherapy with the combination of cytarabine and an anthracycline (7 + 3) is considered the standard of care for intensive induction in AML, achieving CR in 60–80% of younger adults and 40–60% of older adults [8, 9]. After induction therapy, intensive post-remission chemotherapy is often used, and it is comprised high-dose therapy followed by stem cell transplant. HiDAC for up to 4 cycles is utilized widely [8]. After intensive post-remission chemotherapy, the decision to pursue aSCT depends on the risk-benefit ratio based on prognostic factors including patient characteristics and cytogenetic/molecular features. aSCT is generally recommended when the risk of relapse is greater than 35% [8]. The risk of relapse is primarily based on the European LeukemiaNet (ELN) criteria for favorable, intermediate, and adverse risk disease [8]. For favorable risk disease, there is a reported 3-year OS rate of 66% for patients younger than 60 years and 33% in patients older than 60 years [10]. Lo et al. [11] described a CR rate of 93.9%, 77.1%, and 59.8% as well as a relapse rate of 37.8%, 60.7%, and 51.9% in patients with favorable, intermediate, and adverse risk disease, respectively, treated with standard induction chemotherapy. Once relapse occurs, hematopoietic stem cell transplant is usually needed for cure [12].

In relapsed patients who can tolerate it, the general approach to treatment is aSCT after salvage therapy which often depends on cytogenetic and mutational analysis. This aims to serve as a bridge to transplantation by seeking morphological and molecular remission. There is no standard regimen for salvage therapy although FLAG-IDA is a common regimen which includes fludarabine, HIDAC, idarubicin, and granulocyte colony-stimulating factor [13]. This regimen may achieve CR in approximately half of refractory/relapsed (r/r) AML patients, although OS is still only around 15 months [14, 15]. Both non-targeted and targeted therapies have been studied for r/r disease with mixed results.

Our patient relapsed after 7 + 3 induction therapy and 4 cycles of HIDAC. He was reluctant to further pursue intensive chemotherapy. aSCT was presented to him as an option, but he declined. For patients who have failed intensive chemotherapy, nonintensive regimens such as HMAs with or without venetoclax and/or supportive care may be considered as part of a palliative approach [4, 8, 16‒18]. Our patient elected to pursue treatment with azacitidine monotherapy.

Azacitidine and decitabine are cytidine nucleoside analogs that mimic cytosine during DNA replication. These drugs trigger the degradation of DNA methyltransferases, potentially leading to restoration of tumor suppressor genes, cell cycle control, and DNA repair [19, 20]. HMA alone or in combination with other drugs has been used as maintenance therapy for AML [21‒24]. In a phase III randomized trial conducted by Fenaux et al. [24], when compared to conventional care regimens including best supportive care, low-dose cytarabine, or intensive chemotherapy, elderly patients with low marrow blast count (median marrow blasts 23%) who received azacitidine had a median OS of 24.5 months compared with 16.0 months [25]. It is important to note that our patient had only 3% blasts on bone marrow biopsy prior to initiation of azacitidine therapy and perhaps lower burden of disease influenced his response to azacitidine.

Data for patients with relapsed AML treated with HMA monotherapy are scant, although the prognosis remains dismal given that in treatment-naive patients, azacitidine monotherapy only achieves a median OS of 10.4 months [26]. The majority of elderly patients become refractory or relapse after nonintensive therapy and few can be cured [13, 26]. One review using an international multicenter database studied 655 patients with r/r AML treated with azacitidine or decitabine. Median OS was 6.7 months with 16% of patients achieving CR or CR with incomplete count recovery [27]. Another study including both patients with newly diagnosed AML and relapsed AML treated with azacitidine found an OS of 10 months in the previously treated cohort [28]. Similarly, Ritchie et al. [29] studied both patients with newly diagnosed and r/r AML treated with decitabine, describing a CR rate of 15.7% and median OS of 5.8 months.

Our patient had and continues to have a durable response to azacitidine monotherapy which is likely mediated by favorable responses of inv(16) AML to hypomethylating agents. One intriguing detail to point out is that the myeloblast populations identified in the two bone marrow biopsies had different surface flow markers, indicating the possibility of a new AML clone that may have led to relapse. Furthermore, as mentioned above, cytogenetic analysis performed on the patient’s bone marrow cells revealed that there was persistent inv(16). Approximately half of patients with AML have distinct chromosomal translocations or deletions/additions that contribute to AML pathogenesis and prognosis [30, 31]. Inv(16) is one of the most common translocations associated with AML, and it tends to correlate with a higher rate of CR and OS [6, 32‒35]. There are very scant data on low-dose HMA monotherapy in AML patients with inv(16), which was the regimen used for our patient. One study analyzing AML patients with either t(8;21) or inv(16) suggests that HMAs may be used in the maintenance setting in patients who have residual disease after induction/consolidation therapy but may not be effective in those with high levels of residual disease [36].

One explanation for our patient’s clinical course may be the harboring of a point mutation in a particular gene that predisposed him to having such a remarkable response. Next generation sequencing was not performed in our patient; thus, we are not aware of any mutations that would affect his prognosis or explain his response to azacitidine. Coombs et al. [37] showed that in patients with AML harboring a mutation in one of the genes regulating DNA methylation, DNMT3A, there was a higher CR rate when treated with HMAs in the frontline setting. Interestingly, this study also showed that patients with AML who had mutations in nucleophosmin (NPM1) concurrently with mutations in DNMT3A had a higher CR rate when treated with HMAs in both the frontline and r/r settings [30, 37, 38]. Döhner et al. [23] showed the efficacy of azacitidine monotherapy in the maintenance setting in patients with AML who had NPM1 mutations, showing an increase in relapse-free survival and OS. It should be stated that this study only included patients who achieved CR/CRi after induction with or without consolidation therapy which contrasts with our patient’s clinical course. Nonetheless, without next generation sequencing, we cannot rule out the possibility of our patient’s AML harboring a mutation in an epigenetic regulator like DNMT3A or NPM1, which potentiated the efficacy of treatment with azacitidine. Moreover, there is some evidence which suggests that HMAs can modulate the tumor microenvironment by upregulating immunogenic receptors on natural killer cells and dendritic cells and possibly, activating T cells as well [20, 39]. Thus, it is possible that in our patient, azacitidine induced a robust immune response that has incredibly led to his extended survival.

In follow-up visits, our patient’s blood counts have remained normal and he continues on azacitidine monotherapy. A repeat inv(16) analysis was never ordered on peripheral blood but for future cases, this may be a way to monitor for disease recurrence as a way to monitor minimal residual disease.

We are not aware of any other reports of relapsed AML treated with low-dose HMA monotherapy with such an excellent OS. The duration of response has been remarkable and implies mechanism other than cytotoxicity. Further research should seek to characterize the effects of HMA monotherapy on various subgroups of AML, including inv(16). The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000545569).

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Ethical approval is not required for this study in accordance with local or national guidelines.

The authors have no conflicts of interest to declare.

There were no sources of funding in relation to this work.

Chetan Jeurkar: helped and helped edit the manuscript and is the corresponding and first author. Amry Majeed: helped write the manuscript. Margaret Kasner: primary mentor and primary editor of the manuscript. Gina Keiffer and Lindsay Wilde: faculty at Thomas Jefferson University and members of the leukemia team who helped edit this manuscript prior to submission.

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.