Blood Res 2022; 57(3):
Published online September 30, 2022
https://doi.org/10.5045/br.2022.2022060
© The Korean Society of Hematology
Correspondence to : Byung-Sik Cho, M.D., Ph.D.
Department of Hematology, Leukemia Research Institute, Seoul St. Mary’s Hematology Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea
E-mail: cbscho@catholic.ac.kr
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background
Arsenic trioxide (ATO) is the standard treatment for relapsed acute promyelocytic leukemia (APL). However, consensus on post-remission therapies is still lacking.
Methods
We evaluated 52 patients who experienced relapse following initial treatment of APL between 2000 and 2019 at Catholic Hematology Hospital. Among them, 41 patients received reinduction treatment, 30 with ATO-based regimen, whereas 11 with conventional intensive chemotherapy (IC).
Results
The ATO reinduction group showed a significantly higher second molecular complete remission (mCR2) rate, superior neutrophil and platelet recovery, and a lower infection rate than the IC reinduction group. No significant differences were observed in survival outcomes after post-remission treatment among the ATO-based (N=19), autologous (N=12), and allogeneic (N=6) hematopoietic stem cell transplantation (HSCT) groups. In the ATO-based and autologous HSCT groups, among patients with mCR2 after ATO reinduction, nine and five patients experienced a second relapse, respectively (50.7% vs. 41.7%, P=0.878). Among these patients, seven received salvage allogeneic HSCT; six remained alive. The other seven patients received ATO without HSCT. Five died from disease progression, and two survived and have been in mCR2 since.
Conclusion
Post-remission treatment outcomes of patients with relapsed APL were not significantly different, regardless of the treatment option, suggesting the feasibility of ATO-based treatment without HSCT in mCR2. Allogeneic HSCT may be an effective salvage treatment modality for patients with a second relapse. Owing to a few cases of relapsed APL, multicenter prospective studies may help elucidate the efficacy of each post-remission treatment.
Keywords Acute promyelocytic leukemia, Relapse, Arsenic trioxide, Stem cell transplantation, Post-remission therapy
Blood Res 2022; 57(3): 197-206
Published online September 30, 2022 https://doi.org/10.5045/br.2022.2022060
Copyright © The Korean Society of Hematology.
Gi-June Min1, Byung-Sik Cho1, Sung-Soo Park1, Silvia Park1, Young-Woo Jeon2, Seung-Ah Yahng3, Seung-Hawn Shin4, Jae-Ho Yoon1, Sung-Eun Lee1, Ki-Seong Eom1, Yoo-Jin Kim1, Seok Lee1, Chang-Ki Min1, Seok-Goo Cho1, Jong Wook Lee1, Hee-Je Kim1
Department of Hematology, 1Seoul St. Mary’s Hematology Hospital, College of Medicine, The Catholic University of Korea, 2Yeouido St. Mary’s Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, 3Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, 4Eunpyeong St. Mary’s Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
Correspondence to:Byung-Sik Cho, M.D., Ph.D.
Department of Hematology, Leukemia Research Institute, Seoul St. Mary’s Hematology Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea
E-mail: cbscho@catholic.ac.kr
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background
Arsenic trioxide (ATO) is the standard treatment for relapsed acute promyelocytic leukemia (APL). However, consensus on post-remission therapies is still lacking.
Methods
We evaluated 52 patients who experienced relapse following initial treatment of APL between 2000 and 2019 at Catholic Hematology Hospital. Among them, 41 patients received reinduction treatment, 30 with ATO-based regimen, whereas 11 with conventional intensive chemotherapy (IC).
Results
The ATO reinduction group showed a significantly higher second molecular complete remission (mCR2) rate, superior neutrophil and platelet recovery, and a lower infection rate than the IC reinduction group. No significant differences were observed in survival outcomes after post-remission treatment among the ATO-based (N=19), autologous (N=12), and allogeneic (N=6) hematopoietic stem cell transplantation (HSCT) groups. In the ATO-based and autologous HSCT groups, among patients with mCR2 after ATO reinduction, nine and five patients experienced a second relapse, respectively (50.7% vs. 41.7%, P=0.878). Among these patients, seven received salvage allogeneic HSCT; six remained alive. The other seven patients received ATO without HSCT. Five died from disease progression, and two survived and have been in mCR2 since.
Conclusion
Post-remission treatment outcomes of patients with relapsed APL were not significantly different, regardless of the treatment option, suggesting the feasibility of ATO-based treatment without HSCT in mCR2. Allogeneic HSCT may be an effective salvage treatment modality for patients with a second relapse. Owing to a few cases of relapsed APL, multicenter prospective studies may help elucidate the efficacy of each post-remission treatment.
Keywords: Acute promyelocytic leukemia, Relapse, Arsenic trioxide, Stem cell transplantation, Post-remission therapy
Table 1 . Baseline characteristics of patients with relapsed APL (N=52)..
Characteristics | N (%) |
---|---|
At diagnosis | |
Age at diagnosis, median (range) | 39 yr (17–74) |
Gender, male | 32 (61.5%) |
Sanz risk, at diagnosis | |
High | 28 (53.8%) |
Intermediate | 13 (25.0%) |
Low | 11 (21.2%) |
No | 23 (44.2%) |
8 (15.4%) | |
3 (5.8%) | |
16 (30.8%) | |
18 (34.6%) | |
Karyotype abnormalityc) | |
t(15;17) alone | 28 (53.9%) |
t(15;17) with 1 additional karyotype | 5 (9.6%) |
t(15;17) with ≥2 additional karyotype | 14 (26.9%) |
Bleeding tendency at diagnosisd) | 41 (78.8%) |
Coagulopathy at diagnosise) | 46 (88.5%) |
Laboratory findings at diagnosis, median (range) | |
Leukocyte (109/L) | 11.44 (0.58–177.04) |
Hemoglobin (g/dL) | 9.4 (4.0–14.0) |
Platelet (109/L) | 29.0 (4.8–210.0) |
457.0 (6.1–2520.0) | |
Differentiation syndrome | 10 (19.2%) |
At first relapse | |
Age at relapse (median) | 41 yr (19–75) |
CR1 duration, median (range), mof) | 20.7 (5.1–84.3) |
APL 1st relapse type | |
Hematologic relapse | 24 (46.2%) |
Cytogenetic relapse | 6 (11.5%) |
Molecular relapse | 22 (42.3%) |
Laboratory findings, at relapse, median (range) | |
Leukocyte (109/L) | 3.47 (0.52–54.7) |
Hemoglobin (g/dL) | 11.8 (4.0–15.6) |
Platelet (109/L) | 96.0 (7.0–330.0) |
329.5 (2.21–2400) | |
Sanz risk at relapseg) | |
High | 5 (20.8%) |
Intermediate | 5 (20.8%) |
Low | 14 (58.4%) |
Patients who received reinduction therapy | 41 out of 52 patients |
Arsenic-based regimenh) | 30 (57.6%) |
ATO only | 27 (90.0%) |
ATO+ATRA | 3 (10.0%) |
Conventional chemotherapy | 11 (21.2%) |
IDA+ARA | 7 (63.6%) |
IDA+ATRA | 2 (18.2%) |
MTZ+ARA | 1 (9.1%) |
LDARA/etoposide | 1 (9.1%) |
a)
Abbreviations: APL, acute promyelocytic leukemia; ARA, cytarabine; ATRA, all-trans retinoic acid; BCR, breakpoint cluster region; CR, complete remission; ECOG, Eastern cooperative oncology group performance status; FLT3, FMS-related tyrosine kinase; IDA, idarubicin; ITD, internal tandem duplication; LDARA, low dose cytarabine; MTZ, mitoxantrone; PML-RAR
Table 2 . Characteristics and response according to reinduction regimens (N=41)..
Arsenic-based regimen (N=30)a) | Conventional cytotoxic regimen (N=11)b) | ||
---|---|---|---|
Characters | |||
Age (median) | 39.5±2.3 | 39.4±3.5 | 0.969 |
Gender (male) | 18 (60.0%) | 5 (45.5%) | 0.489 |
Sanz risk at diagnosis (high risk) | 21 (70.0%) | 2 (18.2%) | 0.011 |
Sanz risk at relapse (high risk) | 3 (10.0%) | 2 (18.2%) | 0.127 |
Relapse type | |||
Hematologic relapse | 10 (33.3%) | 9 (81.8%) | 0.006 |
Cytogenetic relapse | 2 (6.7%) | 2 (18.2%) | 0.288 |
Molecular relapse | 18 (60.0%) | 0 (0.0%) | 0.001 |
Response | |||
Neutrophil recovery | 19.3±2.9 | 31.1±3.5 | 0.017 |
Platelet recovery | 7.1±2.3 | 25.3±2.8 | <0.01 |
Response type | |||
Overall CR | 30 (100%) | 9 (81.8%) | 0.067 |
Hematologic CR2 | 4 (13.3%) | 1 (9.1%) | 1.000 |
Cytogenetic CR2 | 9 (30.0%) | 6 (54.5%) | 0.272 |
Molecular CR2 | 17 (56.7%) | 2 (18.2%) | 0.029 |
Death in aplasia | 0 (0.0%) | 1 (9.1%) | 0.268 |
Reinduction failurec) | 0 (0.0%) | 1 (9.1%) | 0.268 |
Time to CR2, days | 48.7±3.6 | 39.4±7.2 | 0.263 |
CR2 without death | 30 (100%) | 9 (81.8%) | 0.017 |
Adverse events | |||
Neutropenia, Gr. III–IV | 23 (76.7%) | 11 (100.0%) | 0.160 |
Thrombocytopenia, Gr. III–IV | 9 (30.0%) | 11 (100.0%) | <0.01 |
Infection & FUO | 11 (36.7%) | 11 (100.0%) | <0.01 |
Leukocytosis | 3 (10.0%) | 0 (0.0%) | 0.551 |
Hepatopathy | 11 (36.7%) | 6 (54.5%) | 0.476 |
Differentiation syndrome | 2 (6.7%) | 0 (0.0%) | 0.388 |
a)Among 30 patients, 27 patients (90.0%) received ATO only, and three (10.0%) received ATO+ATRA. b)Among 11 patients, 7 (63.6%) received IDA+ARA, and 2 (18.2%) received the IDA+ATRA regimen. The other two received MTA+ARA and LDARA/Etoposide. c)This patient experienced reinduction failure and died later because of disease progression..
Abbreviations: ATO, arsenic trioxide; ATRA, all-trans-retinoic acid; CNS, central nerve system; CR, complete remission; FUO, fever of unknown origin; IC, intensive chemotherapy..
Table 3 . Characteristics and outcomes according to post-remission treatment (N=37)a)..
ATO-based post-remission (N=19) | Autologous HSCT (N=12) | Allogeneic HSCT (N=6) | ||
---|---|---|---|---|
Age, years (mean±SD) | 40.9±14.8 | 34.8±11.0 | 41.2±10.4 | 0.362 |
Gender, male | 10 (52.6%) | 8 (66.7%) | 4 (66.7%) | 0.685 |
Sanz risk at diagnosis (High risk) | 13 (68.4%) | 5 (41.7%) | 3 (50.0%) | 0.320 |
Sanz risk at relapse (High risk) | 3 (15.8%) | 0 (0%) | 1 (16.7%) | 0.407 |
CR1 duration, months (mean±SD) | 23.1±11.4 | 19.4±11.5 | 21.8±12.3 | 0.697 |
Early relapse ≤1 year | 2 (10.5%) | 5 (41.7%) | 3 (50.0%) | 0.063 |
Type of relapse | ||||
Hematologic relapse | 6 (31.6%) | 6 (50.0%) | 5 (83.3%) | 0.081 |
Cytogenetic relapse | 3 (15.8%) | 0 (0%) | 0 (0%) | 0.213 |
Molecular relapse | 10 (52.6%) | 6 (50.0%) | 1 (16.7%) | 0.288 |
Leptomeningeal relapse | 10 (52.6%) | 7 (58.3%) | 4 (66.7%) | 0.825 |
Consolidation regimens | 0.009 | |||
Arsenic-based consolidation | 19 (100%) | 9 (75.0%) | 3 (50.0%) | |
Anthracycline-based consolidation | 0 (0%) | 3 (25.0%) | 3 (50.0%) | |
Best response | ||||
Hematologic CR2 | 0 (0%) | 0 (0%) | 1 (16.7%) | 0.070 |
Cytogenetic CR2 | 0 (0%) | 0 (0%) | 5 (83.3%) | <0.001 |
Molecular CR2 | 19 (100%) | 12 (100%) | 0 (0%) | <0.001 |
Follow-up period from relapse, months (mean±SD) | 67.9±56.3 | 53.9±50.5 | 62.6±57.2 | 0.791 |
Survival outcomes | ||||
Overall survival | 64.9% (37.6–82.6) | 75.0% (40.8–91.2) | 66.7% (19.5–90.4) | 0.874 |
Disease-free survival | 44.1% (20.9–65.2) | 50.0% (20.8–73.6) | 66.7% (19.5–90.4) | 0.891 |
Cumulative incidence of 2nd relapse | 50.7% (24.8–71.8) | 41.7% (13.9–67.9) | 0% | 0.183 |
Non-relapsed mortality | 5.3% (0.3–22.0) | 10.0% (0.5–37.4) | 33.3% (3.2–70.4) | 0.179 |
Treatment after 2nd relapse | N=9 | N=5 | N=0 | 0.577 |
Arsenic-based treatment only | 4 (44.4%) | 3 (60.0%) | 0 (0%) | |
Salvage allogeneic HSCT | 5 (55.6%) | 2 (40.0%) | 0 (0%) |
a)Among 41 patients who receivedreinduction treatment, one patient died during reinduction due to infectious complications, the other patient died due to refractory disease, and another two patients underwent IC consolidation only (one died after achieving CR due to septic shock, and the other patient received ATO-based reinduction and consolidation after experiencing the 2nd relapse and was alive). Therefore, 37 patients were included in the analysis..
*Patients who achieved mCR2 with negative PML-RAR
Abbreviaions: ATO, arsenic trioxide; CR, complete remission; HSCT, hematopoietic stem cell transplantation..
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