Treatment-free remission after imatinib discontinuation in patients with chronic myeloid leukemia

doi:10.3969/j.issn.1674-8115.2022.10.006

Abstract

Abstract:

Objective ·To analyze the outcomes of treatment-free remission (TFR) after imatinib discontinuation in patients with chronic myeloid leukemia in chronic phase (CML-CP) who meet the criteria for TFR and are willing to monitor the disease regularly, the prognostic factors and the application of droplet digital polymerase chain reaction (ddPCR) technique in monitoring TFR. Methods ·The patients with CML-CP enrolled in this study were monitored regularly after imatinib discontinuation. Molecular response and relapse were analyzed by quantitative polymerase chain reaction (QPCR) for detection of BCR-ABL transcripts. The lymphocytes subsets pre- and post-imatinib discontinuation were evaluated by flow cytometry. ddPCR was used to detect BCR-ABL and the predictive role in TFR was analyzed. Results ·① Forty-two CML-CP patients who met the criteria for TFR were assessed. With median follow-up time 41(5?93) months, 32 (76.2%) patients maintained TFR.The estimated TFR rate by 12, 24 and 48 months were 85.1%, 75.1% and 70.1%, respectively. Median TFR duration was 41 (2?93) months. The most common adverse event post-discontinuation was musculoskeletal pain of grade Ⅰ?Ⅱ (31.0%). Eight patients achieved deep molecular response (DMR) after restart of imatinib. ②58.3% of patients with continuous positive ddPCR developed molecular relapse after imatinib discontinuation, while none relapsed in those with negative detection (P<0.01). ③ The percentage of CD8⁺CD28^-cells pre-discontinuation was lower, while the percentage of CD4⁺CD25⁺ cells post-discontinuation was higher in relapsed patients than that in TFR patients (6.2% vs 12.6%, P=0.026; 3.2% vs 2.1%, P=0.021). Conclusion ·CML-CP patients who meet the criteria of TFR may successfully maintain TFR after TKI discontinuation. ddPCR may help to predict the outcome of TFR and detect the molecular relapse earlier. Immune regulation by different T cell subsets may play a role in TFR duration to prevent relapse of disease.

Key words: treatment-free remission (TFR), imatinib, prognostic factor, chronic myeloid leukemia (CML), droplet digital polymerase chain reaction (ddPCR), lymphocyte subset

CLC Number:

R557

XU Tianxue, QIAN Ying, LIU Zhanyun, CAI Gang, WU Yingli, LI Junmin, SHEN Zhixiang, ZHOU Li. Treatment-free remission after imatinib discontinuation in patients with chronic myeloid leukemia[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(10): 1413-1419.

Figures/Tables 4

TrendMD

References 16

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Prognostic factor	n	TFR rate/%	P value
Gender
Male	16	63.6±16.6	0.550
Female	26	74.5±9.2
Age
Age of diagnosis<40 years old^①	21	76.3±10.7	0.496
Age of diagnosis≥40 years old^①	21	65.3±12.3
Age of drug withdrawal <40 years old^②	12	60.8±15.8	0.436
Age of drug withdrawal ≥40 years old^②	30	74.2±9.8
Sokal score
Low risk	31	77.4±8.3	0.732
Medium risk	10	56.3±20.1
TKI treatment time^①
<85 months	20	77.3±10.1	0.578
≥85 months	22	64.3±12.6
DMR duration^①
<65 months	21	66.9±11.4	0.578
≥65 months	21	72.6±13.2
Duration of BCR-ABL transcripts not detected^①
<56 months	19	69.7±11.6	0.825
≥56 months	23	70.3±12.2
Is there any fluctuation during DMR
Yes	15	55.0±14.1	0.070
No	27	79.4±9.8

Prognostic factor	n	TFR rate/%	P value
Gender
Male	16	63.6±16.6	0.550
Female	26	74.5±9.2
Age
Age of diagnosis<40 years old^①	21	76.3±10.7	0.496
Age of diagnosis≥40 years old^①	21	65.3±12.3
Age of drug withdrawal <40 years old^②	12	60.8±15.8	0.436
Age of drug withdrawal ≥40 years old^②	30	74.2±9.8
Sokal score
Low risk	31	77.4±8.3	0.732
Medium risk	10	56.3±20.1
TKI treatment time^①
<85 months	20	77.3±10.1	0.578
≥85 months	22	64.3±12.6
DMR duration^①
<65 months	21	66.9±11.4	0.578
≥65 months	21	72.6±13.2
Duration of BCR-ABL transcripts not detected^①
<56 months	19	69.7±11.6	0.825
≥56 months	23	70.3±12.2
Is there any fluctuation during DMR
Yes	15	55.0±14.1	0.070
No	27	79.4±9.8

Cell subset	Relapse group （n=4）	TFR group （n=14）	P value
NK/%	30.0 （17.5‒39.0）	25.5 （6.0‒45.0）	0.609
CD10⁺/%	0.6 （0‒2.1）	0.1 （0‒0.3）	0.142^①
CD3⁺/%	61.5 （52.3‒72.6）	64.5 （45.0‒87.4）	0.650
CD3⁺CD4⁺/%	43.6 （34.1‒47.3）	31.9 （18.9‒44.7）	0.066
CD3⁺CD8⁺/%	17.8 （11.5‒20.8）	24.1 （12.6‒33.2）	0.167
CD19⁺/%	10.0 （4.1‒11.7）	8.3 （4.3‒15.1）	0.964
CD20⁺/%	9.3 （3.5‒13.0）	8.6 （4.0‒15.8）	0.985
CD4⁺CD45^RA+/%	14.2 （1.4‒16.5）	7.8 （2.3‒23.9）	0.389
CD4⁺CD45^RO+/%	25.3 （23.3‒29.1）	18.8 （13.8‒30.6）	0.056
CD4⁺CD25⁺/%	1.9 （0.6‒3.7）	1.0 （0.4‒2.2）	0.613
CD4⁺CD25⁺CD127^low+/%	0.7 （0.4‒1.4）	0.7 （0.1‒1.6）	0.863
CD3⁺HLA^-DR⁺/%	2.2 （1.6‒10.6）	3.7 （0.6‒10.5）	0.785
CD3⁺CD69⁺/%	2.3 （1.5‒4.0）	1.6 （0.3‒12.3）	0.327^①
CD4⁺CD28⁺/%	39.1 （32.6‒44.6）	25.6 （14.0‒38.7）	0.007
CD8⁺CD28⁺/%	10.3 （5.9‒17.1）	10.8 （5.7‒19.8）	0.808
CD8⁺CD28^-/%	6.2 （3.7‒8.2）	12.6 （2.8‒21.6）	0.026^①
CD3⁺cell/（μL^-1）	701 （549‒1 372）	1 154 （293‒2 088）	0.924^①
CD4⁺ cell/（μL^-1）	504 （358‒894）	521 （159‒1 214）	0.774^①
CD8⁺ cell/（μL^-1）	180 （152‒393）	402 （130‒858）	0.098

Cell subset	Relapse group （n=4）	TFR group （n=14）	P value
NK/%	30.0 （17.5‒39.0）	25.5 （6.0‒45.0）	0.609
CD10⁺/%	0.6 （0‒2.1）	0.1 （0‒0.3）	0.142^①
CD3⁺/%	61.5 （52.3‒72.6）	64.5 （45.0‒87.4）	0.650
CD3⁺CD4⁺/%	43.6 （34.1‒47.3）	31.9 （18.9‒44.7）	0.066
CD3⁺CD8⁺/%	17.8 （11.5‒20.8）	24.1 （12.6‒33.2）	0.167
CD19⁺/%	10.0 （4.1‒11.7）	8.3 （4.3‒15.1）	0.964
CD20⁺/%	9.3 （3.5‒13.0）	8.6 （4.0‒15.8）	0.985
CD4⁺CD45^RA+/%	14.2 （1.4‒16.5）	7.8 （2.3‒23.9）	0.389
CD4⁺CD45^RO+/%	25.3 （23.3‒29.1）	18.8 （13.8‒30.6）	0.056
CD4⁺CD25⁺/%	1.9 （0.6‒3.7）	1.0 （0.4‒2.2）	0.613
CD4⁺CD25⁺CD127^low+/%	0.7 （0.4‒1.4）	0.7 （0.1‒1.6）	0.863
CD3⁺HLA^-DR⁺/%	2.2 （1.6‒10.6）	3.7 （0.6‒10.5）	0.785
CD3⁺CD69⁺/%	2.3 （1.5‒4.0）	1.6 （0.3‒12.3）	0.327^①
CD4⁺CD28⁺/%	39.1 （32.6‒44.6）	25.6 （14.0‒38.7）	0.007
CD8⁺CD28⁺/%	10.3 （5.9‒17.1）	10.8 （5.7‒19.8）	0.808
CD8⁺CD28^-/%	6.2 （3.7‒8.2）	12.6 （2.8‒21.6）	0.026^①
CD3⁺cell/（μL^-1）	701 （549‒1 372）	1 154 （293‒2 088）	0.924^①
CD4⁺ cell/（μL^-1）	504 （358‒894）	521 （159‒1 214）	0.774^①
CD8⁺ cell/（μL^-1）	180 （152‒393）	402 （130‒858）	0.098

Cell subset	Relapse group （n=7）	TFR group （n=22）	P value
NK/%	24.3 （16.4‒55.6）	28.2 （7.1‒42.0）	0.926
CD10⁺/%	0.3 （0.1‒2.6）	0.1 （0‒1.1）	0.135
CD3⁺/%	65.4 （23.6‒73.5）	60.6 （36.0‒84.3）	0.800
CD3⁺CD4⁺/%	32.7 （16.5‒43.2）	29.4 （21.5‒49.5）	0.627
CD3⁺CD8⁺/%	21.8 （5.5‒26.6）	21.5 （9.0‒-32.6）	0.881
CD19⁺/%	13.3 （3.8‒17.0）	9.4 （5.9‒54.6）	0.633
CD20⁺/%	10.2 （3.1‒15.8）	9.3 （6.0‒30.4）	0.599
CD4⁺CD45RA⁺/%	9.2 （5.0‒16.8）	8.6 （1.4‒24.7）	0.982
CD4⁺CD45^RO+/%	21.1 （10.0‒25.6）	20.6 （7.9‒33.3）	0.846
CD4⁺CD25⁺/%	3.2 （0.6‒7.3）	2.1 （0.3‒4.8）	0.021
CD4⁺CD25⁺CD127^{low +}/%	1.7 （0.1‒3.2）	1.2 （0.1‒3.4）	0.158
CD3⁺HLA^-DR⁺/%	4.0 （1.5‒10.3）	3.5 （1.0‒22.2）	0.962^①
CD3⁺CD69⁺/%	2.1 （0.6‒6.4）	2.1 （0.2‒6.5）	0.404
CD4⁺CD28⁺/%	32.4 （14.1‒41.6）	26.2 （15.9‒43.1）	0.278
CD8⁺CD28⁺/%	10.0 （5.0‒18.1）	10.6 （4.1‒18.9）	0.622
CD8⁺CD28^-/%	11.8 （0.5‒17.8）	9.0 （0.8‒19.4）	0.862
CD3⁺ cell/（μL^-1）	1 176 （465‒1 995）	1 055 （472‒3 355）	0.886
CD4⁺cell/（μL^-1）	604 （325‒1 205）	547 （244‒1 970）	0.768
CD8⁺cell/（μL^-1）	455 （108‒634）	350 （145‒1 083）	0.694^①