We evaluate whether molecular monitoring of minimal residual disease (MRD) using TCR d (TCRD), TCR g ..... Generally, advanced age of the patient and high WBC .... significance of graft-versus-host disease and pretransplantation minimal ...
American Journal of Hematology 80:181–187 (2005)
Minimal Residual Disease (MRD) Monitoring Using Rearrangement of T-Cell Receptor and Immunoglobulin H Gene in the Treatment of Adult Acute Lymphoblastic Leukemia Patients Tomomi Toubai,1* Junji Tanaka,1 Shuichi Ota,2 Takashi Fukuhara,3 Satoshi Hashino,2 Takeshi Kondo,2 Masaharu Kasai,4 Yasutaka Kakinoki,5 Nobuo Masauzi,6 Masanobu Morioka,7 Tsugumichi Kawamura,8 Hiroshi Iwasaki,9 Masahiro Asaka,2 and Masahiro Imamura1 1
2
Department of Hematology and Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan Department of Gastroenterology and Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan 3 Department of Internal Medicine, Asahikawa City Hospital, Hokkaido, Japan 4 Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan 5 Department of Internal Medicine, Asahikawa Kosei Hospital, Hokkaido, Japan 6 Department of Hematology, Hakodate City Hospital, Hakodate, Japan 7 Department of Internal Medicine, Aiiku Hospital, Tokyo, Japan 8 Department of Internal Medicine, Hakodate Central Hospital, Hakodate, Japan 9 Department of Internal Medicine, Asahikawa Kosei Hospital, Hokkaido, Japan
We evaluate whether molecular monitoring of minimal residual disease (MRD) using TCR d (TCRD), TCR g (TCRG), and immunoglobulin H (IgH) gene rearrangements in the bone marrow (BM) is correlated with clinical events in ALL patients. The 14 patients enrolled in this study included 6 males and 8 females with a median age of 53 years (range, 25–79 years), and the median duration of follow-up was 417 days (range, 57–617 days). The median WBC count was 11.3 · 109/L at diagnosis. All patients had L2 type ALL. Eleven patients had a monoclonal pattern of IgH (7), TCRD (3) and TCRG (1), and 3 patients had two clonal patterns. Eleven of the 14 patients achieved the first complete remission (CR) after the first induction chemotherapy. We analyzed 9 of 11 CR patients who could be examined immediately after induction chemotherapy (including re-induction therapy). Event-free survival (EFS, 0%) and disease-free survival (DFS, 0%) at 1 year in CR patients with MRD level ‡10-3 (n = 3) were significantly lower than those in CR patients with MRD level 103 (n ¼ 3) after were significantly lower than those in CR patients with MRD level 494 159
0.013
>456 132
0.013
3 6
>497 617
0.87
>497 245
0.34
>470 216
0.26
5 4
617 528
0.47
>245 195
0.44
>216 158
0.53
7 2
528 >541
0.20
245 >541
0.11
216 >456
0.14
6 3
528 617
0.14
195 >497
0.26
158 >470
0.19
1 8
320 528
0.43
>548 245
0.31
>537 216
0.28
4 5
>280 617
0.88
>238 245
0.25
>211 216
0.19
MRD positivity was associated with high relapse rates (DFS rate of 0% at 1 year). There have been several molecular investigations of MRD in adult patients with ALL [4–6]. Mortuza et al. used semiquantitative IgH gene analysis in a series of 85 adult patients with precursor B-lineage ALL (B-ALL), checked at 4 time points during the first 24 months of treatment, and showed that MRD positivity was associated with increased relapse rates [12]. Our results generally agree with their results. Interestingly, Ph-positive ALL was not a prognostic factor in this study. Although the scale of this study was small, we thought that this phenomenon might be influenced by STI571 administration. However, we did not detect a significant association between Ph-positive ALL and prognosis. Results of log-rank tests in this study showed that Ph-positivity, sex, immunophenotype, and WBC count at diagnosis were not associated with prognosis or relapse. Generally, advanced age of the patient and high WBC count at diagnosis with acute leukemia are related to poor prognosis. However, MRD level after induction chemotherapy is a better prognostic factor to monitor relapse and classify the groups with good prognosis and poor prognosis. CONCLUSIONS
In conclusion, our data provide evidence that molecular MRD status of BM after induction chemother-
apy is a strong predictor of outcome in adult ALL. MRD status becomes progressively more predictive with the passage of time. There is good agreement between MRD status and clinical outcome in patients receiving chemotherapy.
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