Spontaneous remission of acute myeloid leukaemia

Overview

Acute myeloid leukaemia (AML) is a malignant haematopoietic disorder associated with high mortality, which remains challenging to treat despite therapeutic advances, particularly in older patients with comorbidities and those deemed high-risk. The vast majority of patients require intensive treatment, with consolidation of remission and potential cure often necessitating allogeneic haematopoietic stem cell transplantation. Nevertheless, spontaneous remission of AML is an extremely rare phenomenon, typically of limited duration. Hypotheses regarding the underlying mechanism of spontaneous remission frequently implicate an immune-mediated response, often subsequent to infection. This study reviews available case reports documenting instances of spontaneous remission between 2004 and 2023. In total, 27 cases were identified, with a median patient age of 59 years (range 28–77), of whom 19 were male. The most common AML FAB subtypes were M2 and M4, with a normal karyotype being the most frequently reported cytogenetic finding. The duration of spontaneous remission ranged from 1 to 120 months, with a median of 6 months. Additionally, we briefly report our own experience of spontaneous remission in a 75-year-old woman harbouring a cytogenetic abnormality t(9;11)(p21;q23) and trisomy 8, whose remission has persisted for 48 months to date.

Keywords:

acute myeloid leukaemia – spontaneous remission

AML therapy is highly complex and involves either an intensive or a non-intensive approach [5]. Curative-intent strategies typically comprise intensive induction and consolidation chemotherapy, potentially combined with targeted therapy or allogeneic haematopoietic stem cell transplantation in selected patients. Non-intensive strategies include treatment regimens based on hypomethylating agents and inhibitors of the anti-apoptotic protein B cell lymphoma (BCL2), aiming to prolong the time to progression-free survival while maintaining a good quality of life. Palliative care approach focuses on cytoreduction and supportive measures.

Despite its aggressive nature and advances in drug development, AML remains a challenging disease to manage. Improvements in prognosis and longterm survival –⁠ particularly in the highrisk group –⁠ have been limited.

Nevertheless, spontaneous remission (SR) of AML has been observed in rare cases, occurring in the absence of any specific anti-leukaemic therapy. Although this is an exceptionally uncommon phenomenon, it has been documented repeatedly in the literature. The first reported case dates back to 1878, when regression of leucocytosis was observed in a patient following a severe typhoid infection [6]. To date, more than 100 cases of SR in AML have been reported. SR is usually transient and shortterm, although exceptions do exist. According to available data, the median duration of SR is approximately 5 to 7 months [7,8], with exceptionally rare cases lasting several years [9]. SR is most commonly documented at the morphological level [7], however, cases of cytogenetic and molecular remission have also been reported [10]. Although SR is rare in AML, it represents a significant phenomenon, the underlying mechanism of which remains poorly understood. The immune response triggered by infection, often preceding SR, is considered the predominant factor [7]. To date, the Czech literature lacks a com -⁠ prehensive synthesis of current knowledge and recent SR cases in AML; we therefore analysed published case reports to address this gap.

METHODS

For the purposes of this retrospective analysis, the PubMed database was searched to identify relevant case reports. The following keywords were used: “spontaneous remission” AND “acute myeloid leukaemia” and “spontaneous remission” AND “AML”. Articles published between 2004 and 2023, which focused on adult patients and were available in English or Czech were included. Remission was defined morphologically by the presence of less than 5% blasts in the bone marrow. Eligibility for inclusion also required documented cytogenetic profiling of AML. The following parameters were assessed: patient age, sex, AML subtype according to the French-American-British (FAB) classification, cytogenetic and molecular genetic profile, event preceding SR onset, SR duration, depth of SR, and blood count parameters –⁠ number of leukocytes, platelets, haemoglobin. Additional data –⁠ specifically whether immunoglobulins or cytokine levels before or after SR were measured –⁠ were also evaluated where available. The data were analysed using Microsoft Excel.

RESULTS

A total of 27 cases were included in this analysis. Male patients predominated (19/27; 70.4%) compared with female patients (8/27; 29.6). The cohort ranged in age from 28 to 77 years, with a median age of 59 years. The most frequent AML subtypes according to the FAB classification were AML M2 and AML M4, each recorded in 5 (18.5%) cases. Secondary AML occurred in 4 cases (14.8%), one case each arising from myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia (CMML), essential thrombocythemia-type myeloproliferative neoplasm (MPN-ET), and one case of therapy-related AML (t-AML) following treatment for multiple myeloma.

Cytogenetic data were available for all 27 patients. A normal karyotype was the most frequently observed (10/27; 37.0%), followed a complex karyotype (4/27, 14.8%), trisomy of chromosome 8 (2/27, 7.4%) and translocation t (9;11) /2/27, 7.4%). Molecular abnormalities were reported in 12 patients (44.4%), most commonly including mutations in the isocitrate dehydrogenase 2 (IDH2) gene (3/27, 11.1%) and mutations in the nucleophosmin 1 (NPM1) gene (2/27, 7.4%). The complete available cytogenetic and molecular findings are summarised in Tab. 1. The blood count at diagnosis showed a median leukocyte count of 2.15×10⁹/L (range: 0.2–240.0×10⁹/L), a median platelet count of 84×10⁹/L (range: 14–546×10⁹/L) and a median haemoglobin value of 90 g/L (range: 37–133 g/L).

In the majority of cases, SR was preceded by an infectious episode (19/27, 70.4%). Pneumonia or other respiratorytract infection were the most common (13/19, 68.4% of all infections), followed by soft tissue infections (2/19, 10.5% of all infections), gastrointestinal tract (GIT) infections (2/19, 10.5% of all infections), and, in one case each (1/19, 5.3% of all infections), sepsis or catheter-related bloodstream infection (CRBS).

Events other than infections also preceded the onset of SR. In 3 cases (3/27, 11.1%) this was solely the administration of transfusion product, while in 2 cases (2/27, 7.4%), no clear trigger was identified. SR in AML was also reported in 2 patients following discontinuation of lenalidomide, which had been administered as maintenance therapy for diffuse large B-cell lymphoma and multiple myeloma [11,12]. In 1 case (1/27, 3.7%), SR occurred after administration of a gonadotropin-releasing hormone (GnRH) agonist in a patient diagnosed with both AML and prostate cancer [13].

Overall, 13 patients (13/27, 48.1 %) received transfusion prior to SR onset, of whom 10 cases (10/27, 37%) had a concomitant infection. In 1 patient (1/27, 3.7%), in whom transfusion was also the only documented event prior to SR onset, low-dose corticosteroids were additionally also administered [14]. Corticosteroids were given to a total of 4 patients (4/27, 14.8%) prior to SR onset, either as supportive care [8,14,15] or as part of the treatment of COVID-19 pneumonia [16]. Granulocyte colony-stimulating factor (G-CSF) was administered in one patient (1/27, 3.7%) [17].

Regarding genetic factors, long-term SR lasting more than 10 years has been reported in patient with the t(9;11) translocation [9]. Another patient with a similar cytogenetic profile of AML [23], likewise achieved a durable, even molecular, remission. A separate publication describes a series of AML case reports involving NPM1 mutations and SR [35]; however, it is important to note that NPM1 mutations represent a relatively common AML subtype. Even in the presence of cytogenetic abnormalities typically associated with poor prognosis, such as complex karyotypes, SR may occur, as demonstrated in our analysis. Furthermore, data indicate that patients with normal karyotype (27%) showed a slightly longer median duration of SR, reaching 8 months (range: 1–40 months), compared to 6 months in the overall cohort. One case report described a female patient in whom SR was accompanied by clonal evolution and loss of the complex karyotype; repeated bone marrow examinations in this case also confirmed the presence of haemophagocytosis [19]. No consistent correlation between remission depth and cytogenetic profile has been established [10].

Our retrospective analysis supports and extends the findings of previously published studies summarising the current understanding of SR in AML. The most widely accepted hypothesis for its induction focuses on immune-mediated stimulation, activating the host’s antitumour response. Infectious complications are common in AML, both at diagnosis and during treatment. Čerňan et al. reported that up to 93% of patients receiving induction therapy experience infectious complications [36]. Nevertheless, SR in AML remains an exceptionally rare clinical phenomenon.

CONCLUSION

At present, no definitive theory explains the occurrence of spontaneous remission in acute myeloid leukaemia, nor has any specific factor been identified that can reliably predict its onset or duration. A deeper understanding of the immunological mechanisms driving SR in AML could constitute a significant breakthrough in immunotherapy, particularly in improving its efficacy or enabling the development of novel immunomodulatory strategies. However, the rarity, unpredictability, and temporal variability of SR events make conducting prospective studies virtually impossible. Consequently, a comprehensive understanding of this phenomenon is likely to remain elusive in the near future.