At present, acute promyelocytic leukemia (APL) has changed from a highly fatal disease to a curable disease. Therefore, the pursuit of treating APL is to minimize recurrence rate and achieve long-term survival. The widely accepted postremission therapy of APL is 2-3 cycles of anthracycline containing chemotherapy following retinoic acid (ATRA) and small dose of chemotherapy with methotrexate (MTX) and 6-mercaptopurine (6-MP) as maintenance therapy to 2 years [
The good curative effect in the treatment of APL shows that arsenic inducing apoptosis, arsenic retinoic acid inducing cell differentiation, and chemotherapy drug inducing cytotoxic killing effects can provide different effects and play complementary roles. To minimize recurrence, we designed a maintenance treatment schedule, in which the patients accepted sequential application of retinoic acid, RIF, and chemotherapy with interval lengthened by year after 3 cycles of consolidation chemotherapy. Based on this scheme, the information of those who took this scheme and those who accepted traditional ATRA/CTlow regimen during that period has been analyzed retrospectively. From observing long-term survival, recurrence, and side effects of two groups, we attempt to explore the feasibility of this scheme as the maintenance treatment.
This was a retrospective study of 98 patients with newly diagnosed APL from January 2003 to December 2008 in QiLu Hospital of Shandong University. The diagnosis was based on morphology (promyelocytes on peripheral smear and/or bone marrow) and cytogenetic analysis of t(15; 17) chromosomal translocation and/or PML-RAR
All patients accepted remission induction and consolidation chemotherapy according to their Sanz score [
After achievement of CR1, patients received three courses of sequential consolidation chemotherapy with DA regimen (DNR 40 mg/m2 per day for 3 days and Ara-c 150 mg/m2 per day for 7 days), MA regimen (mitoxantrone 8–10 mg/m2 per day for 3 days and Ara-c 150 mg/m2 per day for 7 days), and HA regimen (homoharringtonine 2 mg/m2 per day for 7 days and Ara-c 150 mg/m2 per day for 7 days). After consolidation chemotherapy, they received maintenance chemotherapy.
In maintenance treatment, 52 patients sequentially took RIF (60 mg/kg
Treatment schedule in study group. ATRA: all-trans retinoic acid; ATO: arsenic trioxide; RIF: Realgar-Indigo naturalis formula; DNR: daunorubicin; MIT: mitoxantrone; HHT: homoharringtonine; Ara-c: cytarabine; CT: chemotherapy.
After compression, all patients received lumbar puncture and intrathecal injection with MTX (10 mg) and Ara-c (50 mg) plus dexamethasone (5 mg) for four times in order to prevent CNS leukemia.
PML/RAR
During treatment, patients accepted a regular monitoring of their blood routine, blood coagulation, hepatic and renal function, and electrocardiogram. And changes of their skin, mucous membranes, and nervous, digestive, respiratory, and cardiovascular systems were observed at the same time. Toxic effects were graded according to the National Cancer Institute’s Common Toxicity Criteria.
Complete remission (CR) was defined according to conventional criteria, including cellular BM blasts and abnormal promyelocytes < 5%, absolute neutrophil count ≥
Statistical analysis was performed by using software SPSS13.0. Rate comparison between two groups was performed by means of
A total of 98 newly diagnosed APL patients who entered CR and accepted postremission therapy were enrolled sequentially in this retrospective study, with a mean ± SD age of
Patients’ characteristics in two groups.
Parameters | Experimental group ( |
Control group ( |
---|---|---|
Gender | ||
Male | 32 | 26 |
Female | 20 | 20 |
Age (years) | 14–63 | 13–65 |
WBC count (×109/L) | ||
≤10 × 109/L | 35 | 30 |
>10 × 109/L | 17 | 16 |
Platelet count (×109/L) | ||
>40 × 109/L | 18 | 16 |
≤40 × 109/L | 34 | 30 |
Sanz score | ||
Low risk | 10 | 8 |
Intermediate risk | 25 | 22 |
High risk | 17 | 16 |
Median follow-up time (months) | 81.5 (20–128) | 80 (18–118) |
Sanz score: low risk, WBC ≤ 10 × 109/L and platelets > 40 × 109/L; intermediate risk, WBC ≤ 10 × 109/L and platelets ≤ 40 × 109/L; high risk, WBC > 10 × 109/L.
Induction chemotherapy according to Sanz score: low risk, ATRA; intermediate risk, ATRA + DNR/DA; high risk, ATRA + DA + ATO; consolidation chemotherapy, DA/MA/HA regimen used sequentially in all patients despite their Sanz scores.
In experimental group of 52 patients, one patient, who belonged to the high-risk subgroup, relapsed and died in 20 months after diagnose, and the other 51 patients were followed up more than 5 years. The Kaplan-Meier OS and DFS survival curves of the intermediate/low-risk and high-risk subgroups are shown in Figures
Kaplan-Meier analysis of overall survival (OS) curve and disease-free survival (DFS) curve according to risk in different groups. (a) OS of the experimental group according to risk stratification; (b) DFS of the experimental group according to risk stratification; (c) OS of the control group according to risk stratification; (d) DFS of the control group according to risk stratification.
In control group, five patients relapsed at 12, 18, 23, 26, and 37 months after diagnosis. Among them, only one belongs to intermediate-risk subgroup, while the other four all belong to high-risk subgroup. Two of them relapsed in central nervous system (CNS). After salvage therapy, the relapsing one in intermediate-risk subgroup and two in high-risk subgroup reachieved complete remission (CR2), while the remaining two relapsing patients in high-risk subgroup died of intracranial hemorrhage and serious infections at 18 and 23 months, respectively. The Kaplan-Meier OS and DFS survival curves of the intermediate/low-risk and high-risk subgroups are shown in Figures
The five-year OS and DFS showed no significant difference between experimental group and control group (
Kaplan-Meier analysis of overall survival (OS) curve and disease-free survival (DFS) curve according to risk in different groups. (a) OS of all patients according to different maintenance therapy; (b) DFS of all patients according to different maintenance therapy; (c) OS of all patients according to risk stratification; (d) DFS of all patients according to risk stratification; (e) OS of high-risk patients according to different maintenance therapy; (f) DFS of high-risk patients according to different maintenance therapy.
Before treatment, the test results of PML/RAR
As shown in Table
Toxicity profile in two groups.
Parameters |
Experimental group ( |
Control group ( |
||
---|---|---|---|---|
Grade | 1-2 | 3-4 | 1-2 | 3-4 |
Neutropenia | 12 | 40 | 14 | 0 |
Liver damage | 6 | 0 | 12 | 3 |
Renal damage | 0 | 0 | 0 | 0 |
Cardiac damage | 0 | 0 | 0 | 0 |
Gastrointestinal symptom | 5 | 0 | 4 | 0 |
Oral ulcer | 0 | 0 | 7 | 0 |
Neutropenia was higher in experimental group (
The rate of treatment-related liver damage in control group was significantly higher than in experimental group (32.61% and 11.54%,
Oral ulcers were also significantly higher in control group (
Other side effects, such as headache and gastrointestinal symptom, were tolerable and easily overcome in two groups.
Although APL is now a curable disease, the relapse rate remains relatively high in patients who have survived remission, especially in high-risk patients. This has also been proved by our long-term follow-up data, in which all patients with high risk showed significant higher relapse rate than those with intermediate/low risk (
To improve DFS, many measures have been attempted including strengthening consolidation chemotherapy, adding ATO in maintenance therapy [
Relapse analysis showed that the overall CIRs in control group with the ATRA/CTlow regimen were 10.9%, while this rate rose to 25% in high-risk subgroup, which is similar to the former reports. It is worth noting that incidence rate of liver dysfunction is up to 32.61% as daily dose of 6-MP was taken 100 mg per day. Patients often had to reduce drug use or accept drug withdrawal with poor tolerance of those adverse reactions. This decreased medication compliance may be an important reason of relapse. Another reason of relapse perhaps is cellular drug resistance induced by leukemic stem cells, which could be eliminated by arsenic trioxide.
Compared with traditional maintenance regimen, this ATRA/RIF/CT regimen showed lower relapse with better tolerance. In our study, although neutropenia was common after using chemotherapy according to the original plan, the whole course of treatment has not been interrupted for the recovery of bone marrow suppression. This neutropenia in some degree is beneficial to reduce the relapse as mentioned above. Besides, RIF shows less hepatotoxicity or liver dysfunction when it is taken at maintenance therapeutic dose (60 mg/kg·d), remarkably lower than the dose in inducing therapy (120 mg/kg·d), which shows gastrointestinal reactions in different degrees [
The survival curve analysis showed that the recurrence peak was in 2 years after CR, which indicated that this period was critical to reduce relapse. This is why the treatment cycle was maintained for 2 years. During these 2 years, patients using ATRA/RIF/CT regimen only need to accept 3-cycle chemotherapy in hospital, while other therapies are all taken orally outside the hospital. This regimen could reduce the hospitalization days and costs and get a good efficiency cost ratio. As there was a longer treatment intermittent after one course of treatment, this regimen could keep organism sensitive to chemotherapy drugs and avoid the accumulation of arsenic poisoning. And in that interval, various organ and immune functions of body could be restored to keep the continuity of treatment.
In this study, our repeated sequential therapeutic regimen to APL with ATRA, RIF, and chemotherapy shows better efficacy and less toxicity, especially in high-risk patients. However, our findings should be interpreted with caution because of two limits; one limit is that our study is retrospective and the other is that the study is based on a single-center experience. We need further long-term follow-up studies to explore its curative effect as a more long-term maintenance treatment.
The authors declare that there is no conflict of interests regarding the publication of this paper.
This work was supported by Grants from the Research Award Fund for Outstanding Middle-Aged and Young Scientist of Shandong Province, China (no. 2010BSE27061), the Foundation of Shandong Provincial Science and Technology Development Program (no. 2011YD19009), the China Postdoctoral Science Foundation (no. 2011M501144), and the Foundation of Shandong Provincial Health Scientific Development Program (no. 2011QZ010).