Advances of ATRA combined with arsenic in the treatment of acute promyelocytic leukemia

Feng Liu, Min Dong, Ding-Hua Xiao

Department of Hematology，Affiliated Hospital of Guilin Medical University，Guilin，Guangxi，541001

Keywords:

A BSTRACT

As a distinct subtype of acute leukemia, acute promyelocytic leukemia(APL) has a unique cytogenetic change that is the fusion gene of APL gene on chromosome 15 and retinoic acid receptorα(PML-RARα) on chromosome 17[1]. All-trans retinoic acid(ATRA) and arsenic have a good synergistic effect on the rapid degradation of PML-RARα, which strongly supports ATRAarsenic as the necessary treatment guideline for APL in the world in recent years[2-3]. ATRA-arsenic in the therapy of APL as a model of synergistic targeted therapy of malignant tumors，so scholars in the world have published some new achievements of clinical research in the international mainstream medical journals in recent years, which are summarized as follows.

1. Case individual report

Some special APL patients, including APL patients with other serious diseases and secondary APL patients, were treated with ATRA-arsenic trioxide (ATO) regimen in recent years. The distinctive adverse reactions induced by ATRA or arsenic，namely ocular differentiation syndrome，were mainly seen in case individual reports.

1.1 Other serious diseases

The efficacy and safety of ATRA-arsenic in APL patients with other serious diseases have been confirmed. For example, Peterlin P reported that a 45-year old male APL patient, who had undergone kidney and lungs transplantation has survived after being treated with ATRA-ATO[4].Japanese researchers reported that a 55-year old male APL patient, who received hemodialysis for polycystic kidney disease 17 years ago, began to receive ATRA, but the molecular genetics was not remission before being made by ATRA-ATO to receive molecular genetics complete remission[5].

1.2 Secondary APL patients

The secondary APL patients were treated with ATRA-arsenic, which showed certain curative effect. For example, Jain P reported that a 50-year old white female patient had APL secondary to the refractory follicular lymphoma after about 17 years of history, and still survived for a long time after the relapse of ATRA-ATO treatment[6]. Recently, a 78-year old male patient with chronic myeloid leukemia (CML) developed APL after 7 years of treatment with dasatinib, accompanied by DIC and primitive cell crisis, which got complete remission with ATRA-ATO[7].

1.3 Distinctive adverse reactions

Differentiation syndrome is a distinctive adverse reaction induced by ATRA and/or ATO, including peripheral edema with weight gain, fever, hypotension, dyspnea, acute renal failure and other clinical manifestations. Newman and other scholars reported that two APL patients with ATRA-ATO developed ocular differentiation syndrome, which is a rare differentiation syndrome[8].These case reports suggest that ATRA-ATO as a first-line treatment is still effective and safe for a small number of special APL patients.

2. Case series study

As a special type of APL, recurrent APL, high-risk APL and children APL have been studied in case series in the global.

2.1 Recurrent or high-risk

Laura C and other researchers reported that 22 APL patients received long-term ATRA-ATO treatment after it recurred, which confirmed the potential efficacy of long-term ATRA-ATO treatment for recurrent APL patients especially in patients with long-term first complete remission[9]. The prognosis of high-risk group is worse than that of low-risk group, the main reason of which is that the early mortality rate related to hemorrhage is higher. According to the consolidation treatment stage of APL0406 study, 10 highrisk APL patients in case series study by Shah G were treated with ATRA-ATO, and those patients were still in remission stage with a median follow-up of 38 months[10]. The case series studies of Chinese scholars confirmed the effectiveness of ATRA-arsenic in the treatment of APL in high-risk group[11].

2.2 Children APL

The efficacy and safety of ATRA-ATO in the treatment of children APL in European larger size of case series study[12]. Similar report can be seen in French scholars'comprehensive evaluation of the tolerance of ATRA-ATO in children APL, further confirming the application value of ATRA-ATO in children APL[13].

3. Clinical control study

Methods of clinical control study include retrospective case-control study, prospective cohort study, clinical randomized control trial and Meta-analysis. The regimens of ATRA-arsenic is mainly compared with ATRA-chemotherapy, ATRA-arsenic plus other drugs.

3.1 Comparison with ATRA-chemotherapy

Similar to ATRA-ATO, ATRA-chemotherapy is also one of the conventional regimens of APL treatment[2], so the comparative study report of both is comprehensive and detailed..

3.1.1 Efficacy and prognosis

A 5-year prospective study found that ATRA-arsenic is superior to ATRA-chemotherapy in the induction phase of newly diagnosed APL[14]. Similar Chinese study have confirmed that only ATRAATO maintenance therapy is related to significantly higher diseasefree survival rate and beneficial to APL patients in low and medium risk groups who achieve complete remission through effective treatment[15]. Another similar retrospective analysis in China also confirmed that all newly diagnosed APL patients at risk of SANZ based on ATRA-ATO as the preferred therapy improved long-term survival rate than ATRA-chemotherapy[16]. Chinese scholars further applied Meta-analysis to 585 patients, including 317 ones in the ATRA-ATO group and 268 ones in the ATRA-chemotherapy group. The analysis showed that ATRA-ATO may be more desirable than standard ATRA-chemotherapy especially in low-to-medium-risk APL patients, but larger size of trials are needed to provide more evidence for high-risk APL patients[17]. A prospective, randomized, multicenter and open Italian-German APL0406 phase III noninferiority trial further confirmed the above conclusions and stated that the advantages of ATRA-ATO over ATRA-chemotherapy increase with time. ATRA-ATO has a greater and longer-lasting anti-leukemia effect than ATRA-chemotherapy in low-to-mediumrisk APL patients[18]. Chinese scholars have found that there are no significant differences in the overall survival rate and disease-free survival rate of the long-term efficacy of ATRA-ATO compared with ATRA-chemotherapy in sequential consolidation maintenance therapy in 70 APL patients, but the side effects and treatment-related mortality of ATRA-ATO are relatively lower[19].

3.1.2 Quality of life

ATRA-ATO also has advantage in the quality of life of APL patients compared with ATRA-chemotherapy. Chinese scholars also confirmed that ATRA-ATO can improve the quality of life for APL patients better than ATRA-chemotherapy this year[20].

3.1.3 Medical cost

The concern about the medical cost of APL is directly related to the needs of patients, doctors, hospitals and medical insurance. Autore F and other scholars have found that ATRA-ATO can reduce hospitalization and blood transfusion support compared with ATRAchemotherapy in recent years[21], which can show that ATRA-arsenic has a significant advantage in the medical cost of APL compared with ATRA-chemotherapy.

3.1.4 Adverse reactions

No matter which type of therapy is used for APL patients, adverse reactions may occur. Secondary malignant neoplasm after APL therapy are serious long-term adverse reactions. A retrospective case-control analysis included 760 newly diagnosed APL patients, of which 10 patients had secondary malignant neoplasm, including 7 patients therapy-related malignant neoplasm(T-MN). The 5-year cumulative incidence of T-MN in ATRA-ATO group and ATRAchemotherapy group was 1.0% and 0.4% (P=0.34), indicating that the use of ATRA-arsenic is not more likely to cause T-MN than ATRA-chemotherapy[16]. Hematology related toxicity such as myelosuppression is one of the common adverse reactions. A casecontrol analysis of 58 adult APL patients in China showed that the incidence of grade 3-4 neutropenia was significantly higher in the ATRA-chemotherapy group than in the ATRA-ATO group(P=0.001)[15]. In general, ATRA-ATO can reduce complications and therapyrelated mortality compared with ATRA-chemotherapy[22].

3.2 Comparison with ATRA-ATO plus other drugs

3.2.1 ATRA-ATO plus chemotherapy

Recent studies have explored whether chemotherapy drugs needs to be added with ATRA-ATO or not in terms of efficacy and adverse reactions. Some Chinese scholars have used a randomized controlled trial to investigate the role of cytarabine in the treatment of pediatric APL patients with ATRA-ATO. It has been confirmed that ATRAATO is safe and effective for pediatric APL patients and Ara-C can be omitted when ATO is used for two courses[23]. According to the risk grouping study in China, ATRA-ATO has obvious advantages over ATRA-ATO plus chemotherapy in the treatment of low-risk group APL, but whether chemotherapy needs to be added with ATRA-ATO for high-risk groups APL is not clear in the study[24]. In 2019, some Chinese scholars believed that it was confirmed that the efficacy and safety of the early switch to ATRA-oral arsenic regimens in high-risk APL patients compared with previous ATRAarsenic plus chemotherapy regimens (China APL07 trial) in clinical controlled studies[25].

3.2.2 ATRA-ATO plus targeted drugs

According to new targeted molecular markers in APL patients, corresponding targeted molecular drugs are added to ATRA-ATO regimen to enhance the efficacy, which has become an important exploration direction in recent years. Prospective clinical trials of 187 newly diagnosed APL patients by researchers such as Abaza Y and others have confirmed the use of ATRA-ATO plus gemtuzumab/ozozimin(Go) to improve responsiveness[26], which has attracted the interest and exploration of domestic scholars[24].

4. Conclusion

In summary, ATRA-arsenic is still the first-line therapeutic regimen for all kinds of APL patients, which is superior or not inferior to ATRA-chemotherapy in terms of efficacy, prognosis, adverse reactions, quality of life, and medical cost and other aspects. Whether chemotherapy must be added into ATRA-arsenic regimen or not needs to be confirmed in further clinical practice research, and ATRA-arsenic combined with new targeted molecular drugs may become an important exploration direction for the therapy of APL patients in the future.