SitemapContact Us
닫기
Search
Advanced Search +
닫기
Quick links
Most Cited Most Read Ahead of Print Archives Go to E-submission

Original Article

Split Viewer

Blood Res 2022; 57(3):

Published online September 30, 2022

https://doi.org/10.5045/br.2022.2022060

© The Korean Society of Hematology

Treatment for relapsed acute promyelocytic leukemia: what is the best post-remission treatment?

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

Author Info. +

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

Received: March 8, 2022; Revised: May 3, 2022; Accepted: June 21, 2022

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.

Abstract

Go to

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

Article

Original Article

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.

Treatment for relapsed acute promyelocytic leukemia: what is the best post-remission treatment?

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

Received: March 8, 2022; Revised: May 3, 2022; Accepted: June 21, 2022

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.

Abstract

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

Fig 1.

Download
Figure 1.Flow chart of acute promyelocytic leukemia patients who relapsed after administration of first-line treatment.
Blood Research 2022; 57: 197-206https://doi.org/10.5045/br.2022.2022060

Fig 2.

Download
Figure 2.Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia based on consolidation regimen.
Blood Research 2022; 57: 197-206https://doi.org/10.5045/br.2022.2022060

Table 1 . Baseline characteristics of patients with relapsed APL (N=52)..

CharacteristicsN (%)
At diagnosis
Age at diagnosis, median (range)39 yr (17–74)
Gender, male32 (61.5%)
Sanz risk, at diagnosis
High28 (53.8%)
Intermediate13 (25.0%)
Low11 (21.2%)
FLT3 mutationa)
No FLT3 mutation23 (44.2%)
FLT3-ITD8 (15.4%)
FLT3-TKD3 (5.8%)
PML-RARα subtypeb)
BCR116 (30.8%)
BCR318 (34.6%)
Karyotype abnormalityc)
t(15;17) alone28 (53.9%)
t(15;17) with 1 additional karyotype5 (9.6%)
t(15;17) with ≥2 additional karyotype14 (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)
PML-RARα RQ-PCR (copies/104 ABL)457.0 (6.1–2520.0)
Differentiation syndrome10 (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 relapse24 (46.2%)
Cytogenetic relapse6 (11.5%)
Molecular relapse22 (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)
PML-RARα RQ-PCR (copies/104 ABL)329.5 (2.21–2400)
Sanz risk at relapseg)
High5 (20.8%)
Intermediate5 (20.8%)
Low14 (58.4%)
Patients who received reinduction therapy41 out of 52 patients
Arsenic-based regimenh)30 (57.6%)
ATO only27 (90.0%)
ATO+ATRA3 (10.0%)
Conventional chemotherapy11 (21.2%)
IDA+ARA7 (63.6%)
IDA+ATRA2 (18.2%)
MTZ+ARA1 (9.1%)
LDARA/etoposide1 (9.1%)

a)FLT3 mutation was not evaluated in 18 (34.6%) patients. b)PML-RARα subtype was not evaluated in 18 (34.6%) patients. c)The 5 (9.6%) patients’ karyotype was not available. d)Bleeding tendency was defined as increased susceptibility to bleeding or bruising in patients diagnosed with APL. Any spontaneous bleeding or bruising in a patient was characterized a bleeding tendency. e)Coagulopathy was defined as any derangement of hemostasis resulting in impaired clot formation in patients diagnosed with APL. Thrombocytopenia, PT/aPTT prolongation, decreased fibrinogen level, or prolonged bleeding time regardless of the bleeding event in a patient was charactierzed as coagulopathy. f)The 12 (23.1%) patients experienced early relapse within a year. g)Sanz risk classification at relapse was applied only to the hematological relapse group (N=24). h)The median duration of the first ATO treatment was 37.0 days (range, 1.0–60.0). ATO reinduction was ceased for one patient one day after infusion because of septic shock. The patient died due to septic shock-induced multiorgan failure..

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-RARα, promyelocytic leukemia-retinoic acid receptor alpha; RQ-PCR, real-time reverse transcriptase quantitative polymerase chain reaction; TKD, tyrosine kinase domain..

Table 2 . Characteristics and response according to reinduction regimens (N=41)..

Arsenic-based regimen (N=30)a)Conventional cytotoxic regimen (N=11)b)P
Characters
Age (median)39.5±2.339.4±3.50.969
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 relapse10 (33.3%)9 (81.8%)0.006
Cytogenetic relapse2 (6.7%)2 (18.2%)0.288
Molecular relapse18 (60.0%)0 (0.0%)0.001
Response
Neutrophil recovery19.3±2.931.1±3.50.017
Platelet recovery7.1±2.325.3±2.8<0.01
Response type
Overall CR30 (100%)9 (81.8%)0.067
Hematologic CR24 (13.3%)1 (9.1%)1.000
Cytogenetic CR29 (30.0%)6 (54.5%)0.272
Molecular CR217 (56.7%)2 (18.2%)0.029
Death in aplasia0 (0.0%)1 (9.1%)0.268
Reinduction failurec)0 (0.0%)1 (9.1%)0.268
Time to CR2, days48.7±3.639.4±7.20.263
CR2 without death30 (100%)9 (81.8%)0.017
Adverse events
Neutropenia, Gr. III–IV23 (76.7%)11 (100.0%)0.160
Thrombocytopenia, Gr. III–IV9 (30.0%)11 (100.0%)<0.01
Infection & FUO11 (36.7%)11 (100.0%)<0.01
Leukocytosis3 (10.0%)0 (0.0%)0.551
Hepatopathy11 (36.7%)6 (54.5%)0.476
Differentiation syndrome2 (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)		P
Age, years (mean±SD)40.9±14.834.8±11.041.2±10.40.362
Gender, male10 (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±11.419.4±11.521.8±12.30.697
Early relapse ≤1 year2 (10.5%)5 (41.7%)3 (50.0%)0.063
Type of relapse
Hematologic relapse6 (31.6%)6 (50.0%)5 (83.3%)0.081
Cytogenetic relapse3 (15.8%)0 (0%)0 (0%)0.213
Molecular relapse10 (52.6%)6 (50.0%)1 (16.7%)0.288
Leptomeningeal relapse10 (52.6%)7 (58.3%)4 (66.7%)0.825
Consolidation regimens0.009
Arsenic-based consolidation19 (100%)9 (75.0%)3 (50.0%)
Anthracycline-based consolidation0 (0%)3 (25.0%)3 (50.0%)
Best response
Hematologic CR20 (0%)0 (0%)1 (16.7%)0.070
Cytogenetic CR20 (0%)0 (0%)5 (83.3%)<0.001
Molecular CR219 (100%)12 (100%)0 (0%)<0.001
Follow-up period from relapse, months (mean±SD)67.9±56.353.9±50.562.6±57.20.791
Survival outcomes
Overall survival64.9% (37.6–82.6)75.0% (40.8–91.2)66.7% (19.5–90.4)0.874
Disease-free survival44.1% (20.9–65.2)50.0% (20.8–73.6)66.7% (19.5–90.4)0.891
Cumulative incidence of 2nd relapse50.7% (24.8–71.8)41.7% (13.9–67.9)0%0.183
Non-relapsed mortality5.3% (0.3–22.0)10.0% (0.5–37.4)33.3% (3.2–70.4)0.179
Treatment after 2nd relapseN=9N=5N=00.577
Arsenic-based treatment only4 (44.4%)3 (60.0%)0 (0%)
Salvage allogeneic HSCT5 (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-RARα RQ-PCR received autologous HSCT, and positive PML-RARα RQ-PCR receivedallogeneic HSCT..

Abbreviaions: ATO, arsenic trioxide; CR, complete remission; HSCT, hematopoietic stem cell transplantation..
Blood Res
Volume 59 2024
Current Issue Archives

Supplementary File

Stats or Metrics

Share this article on

  • line

Related articles in BR

Blood Research

pISSN 2287-979X
eISSN 2288-0011
qr-code Download