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A NOVEL METHOD FOR MINIMAL RESIDUAL DISEASE ANALYSIS IN PHILADELPHIA-NEGATIVE ACUTE LYMPHOBLASTIC LEUKEMIA: MODIFIED BIOMED-2 POLYMERASE CHAIN REACTION FOR IMMUNOGLOBULIN HEAVY CHAIN REARRANGEMENT
Author(s):
Daisuke Katoh
,
Daisuke Katoh
Affiliations:
Hematology,Kobe City Medical Center General Hospital,Kobe,Japan
Momoko Nakamura
,
Momoko Nakamura
Affiliations:
Hematology,Kobe City Medical Center General Hospital,Kobe,Japan
Mari Morita
,
Mari Morita
Affiliations:
Hematology,Kobe City Medical Center General Hospital,Kobe,Japan
Hayato Maruoka
,
Hayato Maruoka
Affiliations:
Clinical Laboratory,Kobe City Medical Center General Hospital,Kobe,Japan
Ayumi Fujimoto
,
Ayumi Fujimoto
Affiliations:
Hematology,Kobe City Medical Center General Hospital,Kobe,Japan
Tomohiro Yabushita
,
Tomohiro Yabushita
Affiliations:
Hematology,Kobe City Medical Center General Hospital,Kobe,Japan
Yoshimitsu Shimomura
,
Yoshimitsu Shimomura
Affiliations:
Hematology,Kobe City Medical Center General Hospital,Kobe,Japan
Yuichiro Ono
,
Yuichiro Ono
Affiliations:
Hematology,Kobe City Medical Center General Hospital,Kobe,Japan
Nobuhiro Hiramoto
,
Nobuhiro Hiramoto
Affiliations:
Cell Therapy,Institute of Biomedical Research and Innovation,Kobe,Japan
Satoshi Yoshioka
,
Satoshi Yoshioka
Affiliations:
Hematology,Kobe City Medical Center General Hospital,Kobe,Japan
Noboru Yonetani
,
Noboru Yonetani
Affiliations:
Hematology,Kobe City Medical Center General Hospital,Kobe,Japan
Akiko Matsushita
,
Akiko Matsushita
Affiliations:
Hematology,Kobe City Medical Center General Hospital,Kobe,Japan
Hisako Hashimoto
,
Hisako Hashimoto
Affiliations:
Cell Therapy,Institute of Biomedical Research and Innovation,Kobe,Japan
Takayuki Ishikawa
Takayuki Ishikawa
Affiliations:
Hematology,Kobe City Medical Center General Hospital,Kobe,Japan
(Abstract release date: 05/18/17) EHA Library. Katoh D. 05/18/17; 182344; PB1630
Daisuke Katoh
Daisuke Katoh
Contributions
PDF Abstract
Abstract

Abstract: PB1630

Type: Publication Only

Background
Recent studies have demonstrated the clinical importance of minimal residual disease (MRD) monitoring in adult acute lymphoblastic leukemia (ALL) as well as pediatric ALL. However, patient-specific polymerase chain reaction (PCR)-based MRD assessment, one of the most commonly recognized methods, is not widely used in clinical practice because it is expensive, time consuming, and technically difficult. Therefore, we modified the BIOMED-2 protocol, PCR for immunoglobulin heavy chain (IgH) rearrangement, to assess MRD in ALL easily and readily in our hospital.

Aims
The aim of this study was to examine the clinical utility of monitoring MRD by the modified BIOMED-2 PCR for IgH rearrangement in patients with Philadelphia-negative (Ph (-)) ALL.

Methods
We enrolled 54 patients diagnosed with Ph (-) ALL between 2006 and 2016 in our hospital. IgH rearrangement was detected in 35 patients using the standard BIOMED-2 PCR protocol. Patients who received palliative chemotherapy, never achieved remission (blasts <5%), or had no follow-up MRD data were excluded. Finally, data from 27 patients with Ph (-) ALL were analyzed. We assessed MRD with the modified BIOMED-2 PCR for IgH using bone marrow samples collected after each chemotherapy session. Patients’ MRD statuses were classified as follows: Early MRDneg, achievement of MRD negativity within 6 weeks after chemotherapy initiation; Late MRDneg, achievement of MRD negativity more than 6 weeks after chemotherapy initiation; or MRDpos, persistent MRD detection during chemotherapy. The endpoint was disease-free survival (DFS), calculated from the date of achieving remission.

Results

The median age was 38 years (16–73), and the median follow-up time was 47 months (4–106). There were 8, 14, and 5 patients with early MRDneg, late MRDneg, and MRDpos, respectively. There were no differences in patient characteristics by bone marrow status, except for the duration to achieving remission (Table 1). There were significant differences in the 3-year DFS rates among patients with early MRDneg, late MRDneg, and MRDpos (100% vs. 72.9% vs. 20%; p<0.001) (Fig. 1). Patients undergoing transplantation had better prognosis than those receiving chemotherapy alone in the late MRDneg group (100% vs. 40%, p=0.028), whereas there was no difference in the early MRDneg group (100% vs. 100%, p=0.48).
Table 1.
Patient characteristics by MRD status as assessed with the modified BIOMED-2 PCR for IgH protocol
Factor
Total
(n=27)
MRDpos
(n=5)
Late MRDneg
(n=14)
Early MRDneg
(n=8)
p-value
Sex, M/F
9/18
1/4
6/8
2/6
0.64
Age >50 years
10
1
6
3
0.87
WBC count risk*
4
1
3
0
0.37
Cytogenetic risk**
4
1
3
0
0.37
Transplantation
16
4
9
3
0.33
CR after 2 cycles***
2
2
0
0
0.03
* WBC risk: B >3 × 104/μL, T >10 × 104/μL.
** Cytogenetic risk: Hypodiploidy, complex karyotype, MLL rearrangement.
*** Achievement of remission after 2 cycles of chemotherapy.
MRD, minimal residual disease; PCR, polymerase chain reaction; IgH, immunoglobulin heavy chain; M, male; F, female; WBC, white blood cell; CR, complete remission.

Conclusion
The modified BIOMED-2 PCR protocol is a highly accurate and reliable method of MRD assessment in adult ALL. It predicted treatment outcomes in adult Ph (-) ALL, and patients with late MRDneg might derive a high survival benefit from allogeneic transplantation. Finally, the accuracy and reliability of the modified BIOMED-2 PCR for IgH were confirmed with a comparison to quantitative real-time PCR for BCR-ABL using samples from patients with Philadelphia-positive ALL (data not shown).

Session topic: 2. Acute lymphoblastic leukemia - Clinical

Keyword(s): Minimal residual disease (MRD), IgH rearrangment, Acute lymphoblastic leukemia

Abstract: PB1630

Type: Publication Only

Background
Recent studies have demonstrated the clinical importance of minimal residual disease (MRD) monitoring in adult acute lymphoblastic leukemia (ALL) as well as pediatric ALL. However, patient-specific polymerase chain reaction (PCR)-based MRD assessment, one of the most commonly recognized methods, is not widely used in clinical practice because it is expensive, time consuming, and technically difficult. Therefore, we modified the BIOMED-2 protocol, PCR for immunoglobulin heavy chain (IgH) rearrangement, to assess MRD in ALL easily and readily in our hospital.

Aims
The aim of this study was to examine the clinical utility of monitoring MRD by the modified BIOMED-2 PCR for IgH rearrangement in patients with Philadelphia-negative (Ph (-)) ALL.

Methods
We enrolled 54 patients diagnosed with Ph (-) ALL between 2006 and 2016 in our hospital. IgH rearrangement was detected in 35 patients using the standard BIOMED-2 PCR protocol. Patients who received palliative chemotherapy, never achieved remission (blasts <5%), or had no follow-up MRD data were excluded. Finally, data from 27 patients with Ph (-) ALL were analyzed. We assessed MRD with the modified BIOMED-2 PCR for IgH using bone marrow samples collected after each chemotherapy session. Patients’ MRD statuses were classified as follows: Early MRDneg, achievement of MRD negativity within 6 weeks after chemotherapy initiation; Late MRDneg, achievement of MRD negativity more than 6 weeks after chemotherapy initiation; or MRDpos, persistent MRD detection during chemotherapy. The endpoint was disease-free survival (DFS), calculated from the date of achieving remission.

Results

The median age was 38 years (16–73), and the median follow-up time was 47 months (4–106). There were 8, 14, and 5 patients with early MRDneg, late MRDneg, and MRDpos, respectively. There were no differences in patient characteristics by bone marrow status, except for the duration to achieving remission (Table 1). There were significant differences in the 3-year DFS rates among patients with early MRDneg, late MRDneg, and MRDpos (100% vs. 72.9% vs. 20%; p<0.001) (Fig. 1). Patients undergoing transplantation had better prognosis than those receiving chemotherapy alone in the late MRDneg group (100% vs. 40%, p=0.028), whereas there was no difference in the early MRDneg group (100% vs. 100%, p=0.48).
Table 1.
Patient characteristics by MRD status as assessed with the modified BIOMED-2 PCR for IgH protocol
Factor
Total
(n=27)
MRDpos
(n=5)
Late MRDneg
(n=14)
Early MRDneg
(n=8)
p-value
Sex, M/F
9/18
1/4
6/8
2/6
0.64
Age >50 years
10
1
6
3
0.87
WBC count risk*
4
1
3
0
0.37
Cytogenetic risk**
4
1
3
0
0.37
Transplantation
16
4
9
3
0.33
CR after 2 cycles***
2
2
0
0
0.03
* WBC risk: B >3 × 104/μL, T >10 × 104/μL.
** Cytogenetic risk: Hypodiploidy, complex karyotype, MLL rearrangement.
*** Achievement of remission after 2 cycles of chemotherapy.
MRD, minimal residual disease; PCR, polymerase chain reaction; IgH, immunoglobulin heavy chain; M, male; F, female; WBC, white blood cell; CR, complete remission.

Conclusion
The modified BIOMED-2 PCR protocol is a highly accurate and reliable method of MRD assessment in adult ALL. It predicted treatment outcomes in adult Ph (-) ALL, and patients with late MRDneg might derive a high survival benefit from allogeneic transplantation. Finally, the accuracy and reliability of the modified BIOMED-2 PCR for IgH were confirmed with a comparison to quantitative real-time PCR for BCR-ABL using samples from patients with Philadelphia-positive ALL (data not shown).

Session topic: 2. Acute lymphoblastic leukemia - Clinical

Keyword(s): Minimal residual disease (MRD), IgH rearrangment, Acute lymphoblastic leukemia

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