Distinctive Features Associated with Differentiation Syndrome in Acute Promyelocytic Leukemia in Patients treated by All-Trans Retinoic Acid and Arsenic Trioxide

doi:10.21203/rs.3.rs-4208835/v1

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Distinctive Features Associated with Differentiation Syndrome in Acute Promyelocytic Leukemia in Patients treated by All-Trans Retinoic Acid and Arsenic Trioxide

https://doi.org/10.21203/rs.3.rs-4208835/v1

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In all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) treatment of acute promyelocytic leukemia (APL), differentiation syndrome (DS) assumes a distinct identity separate from ATRA syndrome, with distinct temporal patterns, diagnostic parameters, and clinical behavior. We retrospectively evaluated single-center data of years 2013–2022. Patients with newly diagnosed APL were categorized into three groups (16 patients in ATRA/ATO standard-risk group, 3 patients in ATRA/chemotherapy standard-risk group, and 5 patients in ATRA/chemotherapy high-risk group). Our aim was to analyze leukocytosis, signs of DS, and hepatic impairment within the first 25 days of treatment. The incidence of DS in the ATRA/ATO SR group was 43.8%, with a median of 4 days and 2 days from ATRA and ATO initiation, respectively. This group also exhibited higher peak levels of leukocytosis 34.5 (6.0-113.4) x10⁹/L (p = 0.0809). ALT elevation was more prevalent in the ATRA/ATO SR group (93.75%), with 68.75% grade 3–4 elevations (p = 0.0094). Importantly, all patients in this group had ALT levels that returned to normal during the subsequent consolidations. These findings suggest hepatopathy as a potential manifestation of ATRA/ATO induced DS. Diverse differentiation patterns were identified within the ATRA/ATO group, classifying patients into three distinct subgroups based on the concurrent dynamics of leukocytes and ALT levels, illustrating simultaneous, sequential, and divergent elevation patterns. These emphasize the different distribution of differentiation syndromes (organs vs. peripheral blood). We introduced real-world data and advocated for reevaluation of the current DS definition and associated diagnostic thresholds.

Acute promyelocytic leukemia

differentiation syndrome

leukocytosis

arsenic trioxide

Differentiation syndrome (DS) is a known complication of acute promyelocytic leukemia (APL) therapy. DS is a diagnostic challenge, often eluding proper recognition with potentially fatal consequences. DS, particularly in the context of the all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) treatment protocol, manifests as a distinct entity separate from the ATRA syndrome. ATRA/ATO demonstrated the unique synergism of these two differentiating agents in terms of divergent temporal patterns, diagnostic parameters, and some clinical behavioral features. Notably, DS was infrequently observed during the era of chemotherapy-based treatments for patients with standard risk (SR) APL (1, 2, 3). The differentiation of acute promyelocytic leukemia blasts under ATRA/ATO treatment seems to follow an exponential pattern, and delayed therapeutic response leads to more significant consequences. Although the Montesinos criteria (4) provide a rigid framework for defining DS, their applicability in the pragmatic management of senior comorbid patients undergoing ATRA/ATO treatment presents limitations. For instance, the rapid accrual of 5 kg in weight, although indicative of DS as per the criteria, may pose considerable challenges for frail individuals with cardiac concerns. Consequently, our goal pivots towards the preemptive avoidance of DS occurrence.

We note that a distinction should be made between leukocytosis, cellular differentiation, and differentiation syndromes. During ATO/ATRA treatment, leukocytosis is observed in 43–72% of patients, with rates reaching up to 100% in children. Notably, this leukocytosis may represent only the tip of the iceberg, and in some patients, differentiation predominantly occurs in the organs. A markedly elevated white blood cell count can be a common laboratory finding in patients with differentiation syndrome according to the ATRA/ATO protocol. However, leukocytosis is not required for the diagnosis of differentiation syndrome, as the condition is primarily defined by clinical symptoms (5, 6). It is noteworthy that during DS episodes, biochemical (e.g., hepatic) and hematological parameters may vary owing to the dispersion of differentiating cells –infiltrated tissues vs. peripheral bloodstream leukocytes. Exacerbation of coagulopathy, hepatic impairment, and mineral imbalances are concomitant phenomena, even though they are not mentioned in the Montesinos criteria. Montesinos initially observed a statistically significant correlation between severe DS and elevated occurrences of thrombosis, hemorrhagic events, and hepatic impairment (4, 7). In post-mortem studies of a patient who succumbed to DS, differentiating cells infiltrating the alveoli, bronchial walls, liver, spleen, kidneys, pancreas, adrenal glands, lungs, testes, myocardium, gastric mucosa, and mucosa of the small and large intestines were observed. With no evidence of leukostasis in these patients, mechanisms other than a simple increase in the leukemic cell number are implicated in the pathogenesis of DS (8).

Intriguingly, emerging data indicate the possibility of hepatopathy serving as a potential ATRA/ATO-DS manifestation (63% in the GIMEMA trial) (5). All of the patients with hepatic impairment due to the first exposure to ATO, had their liver function almost normal after the second administration of ATO during consolidation cycles (9). The work of the authors De et al. (10) confirms that, in the treatment with ATO, there is a significant association between hepatic impairment and an increased leukocyte level. In another study by Chinese authors, the median time to hepatic impairment was 6 days (1–43), and the proposed mechanisms were mitochondrial dysfunction and inflammatory reaction. In addition, the mentioned risk factors are leukocytosis and fibrinogen levels; this risk lowers the use of hepatoprotective agents. The liver is temporarily unable to metabolize arsenic metabolites within a short time, and a complementary increase in liver enzymes is observed (11).

The administration of cytoreductive interventions becomes imperative when leukocyte counts exceed 10 G/L, and prophylactic corticosteroid utilization is indicated when leukocyte counts surpass 5 G/L (12, 13, 14). Notably, DS manifestations often emerge even below these threshold values, and a multiplication rate or doubling time seems to be a more accurate risk parameter. Moreover, DS does not occur at the peak of leukocytes (Le), but during the increment of leukocytes on days 1–2 after ATO initiation (15, 16).

Thus, in our single-center study we collected the dataset of 10 years to analyze the distinctive attributes characterizing ATRA/ATO-induced DS. Through this exploration, we endeavored to enhance the understanding and management of DS, contributing to optimized therapeutic outcomes in APL patients undergoing this effective treatment regimen.

In this retrospective study, we evaluated patient data from the Department of Oncohematology at the National Cancer Institute (NCI) Bratislava, Slovakia, in years 2013–2022. This analysis focused on patients diagnosed with de novo acute promyelocytic leukemia (APL) diagnosis. It is noteworthy to mention that in our Slovak cohort, the administration of ATO has been used in our department since 2017 and is restricted to patients classified as standard risk.

The patient cohort was categorized into three distinct groups based on the treatment protocol and risk stratification.

Group 1 comprised standard-risk cases treated with a regimen involving all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) using the APL0406 protocol (5). Induction regimen: all-trans retinoic acid (ATRA) 45 mg/m2 per day was administered in two divided doses (rounded to the nearest 10 mg increment) starting on day 1 until hematological CR or for a maximum of 60 days. Arsenic trioxide (ATO) 0.15 mg/kg IV was administered over 2 hours daily until hematological CR. ATO was administered in conjunction with all-trans retinoic acid after a median delay of 1.5 (0–6) days, attributed to logistical or diagnostic considerations. Group 2 included high-risk patients undergoing ATRA plus chemotherapy (idarubicin and cytarabine) (PETHEMA LPA2005 protocol) (17), while Group 3 included standard-risk patients subjected to ATRA plus chemotherapy (idarubicin) (PETHEMA LPA2005 protocol) (17). Leukocytosis (> 10 G/L) was treated with additional cytoreductive measures (hydroxycarbamide, idarubicin, cytarabine, and gemtuzumab ozogamicin since 2022) as well as ATO and/or ATRA withdrawal. DS treatment consisted of dexamethasone (10 mg BD), diuretics, and ATO and/or ATRA withdrawal. DS prophylaxis (dexamethasone 4 mg BD) was administered to patients with leukocytes > 5 G/L.

The analysis focused on quantifying patients with leukocytosis (> 10 G/L), differentiation syndrome (DS), and hepatic impairment (notably alanine aminotransferase elevation) within the initial 25 days of treatment. Additionally, our objective was to analyze the temporal relationship between hepatic impairment and leukocytosis or DS symptoms. We also analyzed the lactate dehydrogenase (LDH) level, which serves as a marker of cell turnover and is often associated with DS.

Our analysis included patients who received treatment beyond day 1. Descriptive statistics were used to characterize categorical variables through numerical frequencies and percentages and continuous variables through mean values and range, except for age, reported as median and range.

To explore the temporal association between the initiation of differentiation agents and onset of DS symptoms, we used the log-rank test. Fisher's exact test was used to assess the proportion of patients with DS versus other related parameters.

For the examination of biochemical and hematological parameters during induction, repeated-measures analysis of variance (Kruskal-Wallis test) was conducted. Missing values were imputed using the values from the nearest available day. Statistical significance was determined at a threshold of p < 0.05. We used software tools of MS Excel 365 and NCSS v.11.

Patients’ characteristics

From 2013 to 2022, 24 patients diagnosed with de novo Acute Promyelocytic Leukemia (APL) were enrolled in our center of the Oncohematology Department of the National Cancer Institute Bratislava, Slovakia. The demographic and clinical characteristics of the patients are summarized in Table 1. Ten patients (41.67%) were male and 14 (58.33%) were female. The ages of the patients ranged from 27 to 77 years, with a median age of 50 years. The median age of male patients was 36 years (range, 29–74 years), while that of female patients was 61 years (range, 27–77 years). Of the total patient cohort, 5 individuals (20.83%) were identified as having secondary APL. Regarding risk stratification, five patients (20.83%) were classified as high risk, while the remaining 19 patients (79.17%) were categorized as standard risk.

Table 1

Patient’s characteristics
Parameter (N = 24)	No (min-max) or (%)
Age	50 (27–77)
Median age men 36 (29–74), women 61 (27–77)
Sex
M	10 (41.67%)
F	14 (58.33%)
Secondary APL	5 (20.83%)
Risk stratification
High risk	5 (20.83%)
Standard risk	19 (79.17%)
Induction therapy
Group 1 ATRA/ATO standard risk	16 (66.67%)
Group 2 ATRA/CHT high risk	5 (20.83%)
Group 3 ATRA/CHT standard risk	3 (12.50%)

For induction therapy, patients were divided into three groups based on the treatment protocols:

Group 1 (ATRA/ATO standard risk): 16 patients (66.67%).
Group 2 (ATRA/CHT high-risk): 5 patients (20.83%)
Group 3 (ATRA/CHT standard risk): 3 patients (12.50%)

Notably, Groups 2 and 3 served as control cohorts.

All patients with standard-risk APL achieved molecular remission after induction; in the high-risk group, 1 patient died of cardiac failure within the differentiation syndrome. The incidence of DS did not significantly differ among the treatment groups (7, 2 and 1 patients), with rates of 33.3%, 40.0%, and 43.8% in ATRA/CHT SR, ATRA/CHT HR, and ATRA/ATO SR groups respectively (p = 0.7697), however, there was trend towards higher incidence in ATRA/ATO SR group. Leukocyte peak values showed a trend towards significance, with ATRA/ATO SR group having higher peak levels of 34.5 (6.0-113.4) G/L compared to ATRA/CHT SR - peak of leukocytes 7.8 (4.4–13.3) and ATRA/CHT HR - peak of leukocytes 33.6 (25.6–47.1) G/L groups (p = 0.0809). The time taken to achieve differentiation syndrome (DS) varied slightly across the groups. ATRA/CHT SR had a median time of 4 days (p = 0.3520), ATRA/CHT HR had a median time of 3 days, and ATRA/ATO SR had a median time of 4 days from ATRA initiation and 2 days from ATO initiation. Most ATRA/ATO patients started to differentiate 1–2 days after ATO initiation.

The examination of DS symptoms, as outlined by the Montesinos criteria, was performed in the context of different treatment modalities. Within the groups, patients undergoing ATRA/ATO SR treatment displayed a notably higher occurrence of weight gain exceeding 5 kg (9 patients, 56.3%), peripheral edema (8 patients, 50.0%), dyspnea (9 patients, 56.3%), and fever (4 patients, 25.0%). However, these results were not statistically significant.

Table 2 summarizes the alanine aminotransferase (ALT) values at D1-10 time points during induction across the three groups. Patients in the ATRA/ATO group exhibited higher ALT levels on day 7 (D7), although the difference was not statistically significant. However, by Day 10 (D10), the difference was statistically significant (p = 0.0373), indicating an association between treatment modality and hepatic impairment, especially at later time points. ALT elevation was significantly more prevalent in the ATRA/ATO SR group (15 patients, 93.75%) than in the ATRA/CHT SR (3 patients, 66.7%) and ATRA/CHT HR (3 patients, 60.0%) groups (p = 0.0129). This number was higher than that reported in previous studies. Notably, eleven (68.75%) of ATRA/ATO SR patients experienced grade 3–4 ALT elevation compared to none in the ATRA/CHT SR and ATRA/CHT HR groups (p = 0.0094). We also observed that some patients in the chemotherapy group exhibited elevated ALT levels during the induction phase, albeit to a lesser degree. All 15 patients with ALT elevation had elevated ALT during episodes of DS symptoms or leukocytosis (15/15, 100%), and all had ALT levels approximately normal (≤ 2N) during consequent consolidation therapies.

Table 2

ALT values during induction vs group
	ATRA/ATO SR	ATRA/CHT HR		p
ALT D1+	0.74 (0.17–1.78)	1.06 (0.36–2.12)	0.54 (0.56–0.80)	0.2409
ALT D5+	1.23 (0.23–6.06)	1.26 (0.36–2.52)	0.77 (0.80–1.01)	0.6242
ALT D7+	2.32 (0.26–7.99)	1.25 (0.36–2.71)	0.77 (0.80–1.01)	0.2207
ALT D10+	3.59 (0.38–13.30)	0.94 (0.27–1.52)	1.15 (0.66–1.80)	0.0373*
ALT elevated	15 (93.75%)	3 (60.0%)	2 (66.7%)	0.0129*
G3-4	11 (68.75%)	0	0	0.0094*

Table 3 compares the initial values of ALT, Le, and LDH with respect to the severity of hepatic impairment (graded as G3-4 and G0-2) during induction in the ATO/ATRA group. Higher initial values of ALT (0.81 vs. 0.26) and LDH (5.25 vs. 3.31) were associated with a greater severity of hepatic impairment (G3-4) and the results were statistically significant (p = 0.0108 and p = 0.0474, respectively).

Table 3

Initial values (D1) of ALT, Le, LDH, vs hepatic impairment (ALT elevated) during induction in ATO/ATRA group
	ALT elevated G3-4	ALT elevated G0-2	P
ALT D1	0.81 (0.37–1.78)	0.26 (0.17–0.8)	0.0108*
Le D1	2.25 (0.66–7.99)	0.47 (0.42–7.01)	0.0790
LDH D1	5.25 (3.7–6.96)	3.31 (3.04–5.92)	0.0474*

The graphical representation in Fig. 1 illustrates the Group 1–3 mean values of leukocyte (Le), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) levels across different time points. Notably, the ATO/ATRA group exhibited distinctive patterns, particularly in comparison with their standard-risk chemotherapy counterparts. The ATO/ATRA group demonstrated a higher peak in leukocyte count, indicating a notable variation from their chemotherapy SR counterparts. In the ATO/ATRA group, ALT levels exhibited a peak around D8-11, showing a distinct temporal behavior, and the LDH levels in the ATO/ATRA group were consistently higher, suggesting a sustained difference from their chemotherapy SR counterparts. These observations underscored the unique dynamics of the ATO/ATRA group.

Figure 2 illustrates the diverse response patterns observed in patients undergoing ATRA/ATO treatment, categorizing them into three distinct groups based on the concurrent dynamics of leukocytes and ALT. LDH level indicates the amount of leukocyte turnover. A, B, C represent the laboratory parameters of a typical patient in each group.

A. Simultaneous Elevation (7 patients):

The first subgroup within the ATRA/ATO cohort exhibited a concurrent increase in leukocyte counts and ALT levels. This simultaneous increase suggests the synchronized development of DS in the peripheral blood and liver.

B. Sequential Elevation (4 patients):

In the second subgroup, patients exhibited a sequential pattern wherein ALT levels first increased, followed by a subsequent increase in leukocyte count. This temporal disparity in elevation may signify a greater burden of differentiating leukocytes in tissues/organs as opposed to peripheral blood, possibly reflecting the sequential impact on the hepatic and hematological compartments.

C. Divergent Elevation (4 patients):

The third subgroup displayed a divergent pattern, with patients showing elevation in leukocytes without a corresponding increase in ALT or only a marginal increase. This group suggests a nuanced response, in which the differentiating burden may predominantly influence peripheral blood while minimally affecting the hepatic parameters.

One ATRA/ATO patient did not experience neither leukocytosis nor ALT elevation.

In the years 2013–2017, the PETHEMA LPA2005 protocol was used at our institution. Subsequently, upon the availability of ATO in the Slovak Republic (SR) in accordance with international standards, we adopted the APL0406 protocol. We observed an increased incidence of complications during standard induction treatment for APL compared to chemotherapy. In cases of leukocytosis exceeding 10 × 10 G/L, cytoreduction was administered according to the recommendations of the aforementioned protocol, and ATO and ATRA treatments were discontinued only upon meeting the criteria for Differentiation Syndrome (DS). However, the DS criteria were underestimated, exhibiting a diagnostic threshold that was too high in light of the rapid dynamics of DS development and the fragility of some of our elderly patients with comorbidities.

In the initial case of administering a combination treatment involving ATRA/ATO at our department, our first patient treated with ATRA/ATO did not exhibit DS, increased ALT, or leukocytosis. We believed that this initial outcome represents a promising and uncomplicated therapeutic approach. However, in subsequent cases involving another group of 16 patients, the situation was different, and the majority of these patients experienced one or more complications. The diagnosis of DS is based on the Montesinos criteria, which includes fever, dyspnea with pulmonary infiltrates, weight gain, renal failure, hypotension, and pleuropericardial effusions (4, 19). Figure 3 also shows “non-traditional” DS symptoms, whose early recognition is crucial for timely intervention and improved DS management in patients undergoing ATRA/ATO treatment.

While hepatotoxicity is often reported as an adverse effect of arsenic, further studies are needed to fully understand the relationship between hepatopathy and DS in patients with APL. However, the underlying mechanism is not completely understood. It is possible that the liver, infiltrated with rapidly differentiating cells, will have a temporary problem in metabolizing ATO in a relatively short time. The observed hepatopathy was mostly transient and mild, with the majority of cases falling into the category grade 1–2 in previous studies (5). We noticed higher incidence of this complication in our ATRA/ATO patients, ALT elevation was noticed in 93.75% patients, with grade 3–4 in 68.75% of patients. According to the current recommendations, ATRA/ATO administration should be discontinued in cases of hepatotoxicity ≥ G3, and in the case of other DS symptoms, corticosteroid treatment is recommended. Including hepatopathy in the DS criteria could facilitate early diagnosis and prompt intervention, potentially preventing severe complications.

In our analysis, after the initiation of ATRA/ATO induction, we observed a rapid onset of leukocytosis, hepatopathy, and/or DS, approximately 1–2 days after ATO administration. This phenomenon may be attributed to the distinct mechanisms of ATRA and ATO, which likely lead to a synergistic and accelerated response to differentiation stimuli and subsequent symptoms. In contrast, patients who received ATRA/CHT tended to have a delayed manifestation of DS.

In particular, elderly and frail patients show decreased tolerance to rapid weight gain exceeding 5 kg, leading to subsequent cardiovascular complications. These patients often require DS treatment despite not meeting the traditional criteria for DS. Prompt recognition of DS is essential for establishing appropriate treatment, which consists of dexamethasone and diuretics, as well as the discontinuation of ATRA/ATO (20, 21). The goal of cytoreductive measures is to prevent the endangerment of patients with leukocytosis and DS. There is consensus that cytoreduction should be administered in patients with Le ≥ 10 G/L, as the white blood cell (WBC) count may rapidly escalate, carrying the potential for complications, including differentiation syndrome. Various strategies have been employed, such as combining ATRA-ATO with gemtuzumab ozogamicin (GO), as observed in AML17 and at the MD Anderson Cancer Centre, or with idarubicin, as demonstrated in the Australian APML4 trial (12, 22, 23, 24). Since 2022, our department has favored the use of gemtuzumab ozogamicin (GO) for cytoreduction because of its faster onset of action and shorter duration of cytopenia than chemotherapy-based cytoreduction.

In a recent study analyzing data from 2000 to 2021, there was lower mortality attributed to APL-DS and intracranial hemorrhage in academic centers. Conversely, mortality rates in non-academic centers persisted at elevated levels, highlighting the importance of centralizing care and the early recognition of subtle symptoms by trained personnel (25).

In our center, between 2017 and 2022, we successfully treated 16 patients utilizing the ATRA/ATO regimen. All patients achieved complete molecular remission, and as of January 1, 2024, all patients were alive, and remission persisted. Our retrospective analysis of patients with APL undergoing ATRA/ATO treatment revealed a dynamic landscape of differentiation syndrome (DS) marked by diverse clinical presentations. The observed subgroups of leukocyte and ALT dynamics emphasize the different distribution of differentiation syndromes (organs vs. peripheral blood). These findings underscore the need for a nuanced and personalized approach to DS management considering the varied responses of patients. Moreover, the potential significance of hepatopathy and hepatotoxicity as criteria for diagnosing DS requires further clinical studies.

Acknowledgements

We sincerely thank Professor Dr. Michal Mego, Dr. Sc. for his valuable advice and comment.

Disclosure of Conflicts of Interest

The authors declare no competing financial interests.

Authorship Contributions

Authors Silvia Cingelova and Eva Mikuskova share the first authorship and participated in research design, authors Iveta Oravcova, Alica Slobodova, Vanda Mikudova, Lubos Drgona, Jana Spanikova, Radka Vasickova, Denis Urban and Ludmila Demitrovicova participated in the performance of the research. Silvia Cingelova participated in data analysis, and Silvia Cingelova, Iveta Oravcova, and Eva Mikuskova participated in the writing of the paper. All authors read and approved the final manuscript.

Disclosure of Conflicts of Interest The authors declare no competing financial interests.

Data Availability Statement The data presented in this study are available upon request from the corresponding author.

Ethics approval statement This study was conducted in accordance with the Declaration of Helsinki. The Institutional Review Board of the National Cancer Institute, Bratislava, Slovakia approved this retrospective study (IZLO-1) and waived the requirement for patient consent. (Identification code: DS01).

Funding SourcesThis study was not supported by any sponsor or funder.

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No competing interests reported.

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Distinctive Features Associated with Differentiation Syndrome in Acute Promyelocytic Leukemia in Patients treated by All-Trans Retinoic Acid and Arsenic Trioxide

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Abstract

Figures

Introduction

Materials and Methods

Results

Patients’ characteristics

A. Simultaneous Elevation (7 patients):

B. Sequential Elevation (4 patients):

C. Divergent Elevation (4 patients):

Discussion

Conclusion

Declarations

References

Additional Declarations

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