Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Chao Family Comprehensive Cancer Center, University of California Irvine, Orange, California, USA.
Acta Haematol. 2021;144(3):285-292. doi: 10.1159/000510112. Epub 2020 Nov 25.
The addition of tyrosine kinase inhibitors (TKIs) to chemotherapy has dramatically improved outcomes of patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). When allogeneic hematopoietic stem cell transplant (HSCT) is performed, maintenance TKI is generally given for a fixed duration. However, the optimal duration of TKI outside of HSCT remains unknown, and the common practice is to continue indefinitely. Here, we report characteristics and outcomes of 9 patients treated with chemotherapy + TKI without HSCT and later discontinued TKI.
Among 188 patients with Ph-positive ALL who did not undergo HSCT, 9 of them discontinued maintenance TKI mainly due to side effects. Patients were closely monitored with serial PCR testing for the BCR-ABL1 transcript. Major molecular response (MMR) was defined as BCR-ABL1 transcript ≤0.1% on the international scale for p210 transcripts and a 3-log reduction from baseline for p190 transcripts. Deep molecular remission (DMR) was defined as the absence of quantifiable BCR-ABL1 transcripts with a sensitivity of 0.01%. Molecular relapse was defined as loss of MMR. Treatment-free remission (TFR) was defined from time of TKI discontinuation to molecular relapse, last follow-up, or death from any cause.
At the time of TKI discontinuation, transcript level was undetected in 6 patients, <0.01% in 2 patients, and 0.01% in another patient. Prior to discontinuation, the median duration of TKI therapy and of DMR was 70 and 47 months, respectively. No morphological relapse occurred. Three patients (33%) had molecular relapse at a median of 6 months. All 3 resumed TKI therapy, and 2 of them regained DMR after a median of 13 months. After a median follow-up of 49 months, the median TFR was not reached, and the 4-year TFR rate was 65%. The median duration of DMR in patients with and without molecular relapse was 22 and 58 months, respectively (p = 0.096).
TKI discontinuation outside of HSCT in Ph-positive ALL in the setting of compelling toxicity may be safe only among a highly selected group of patients with deep and prolonged DMR undergoing close and frequent monitoring. Validation of these findings in prospective clinical trials is highly needed.
酪氨酸激酶抑制剂（TKI）联合化疗显著改善了费城染色体（Ph）阳性急性淋巴细胞白血病（ALL）患者的预后。当进行异基因造血干细胞移植（HSCT）时，通常会给予固定时间的维持 TKI。然而，HSCT 之外 TKI 的最佳持续时间尚不清楚，通常的做法是无限期地继续使用。在此，我们报告了 9 例未接受 HSCT 而接受化疗+TKI 治疗后停用 TKI 的患者的特征和结局。
在未接受 HSCT 的 188 例 Ph 阳性 ALL 患者中，有 9 例因副作用而停用维持 TKI。通过连续 PCR 检测 BCR-ABL1 转录本对患者进行密切监测。主要分子缓解（MMR）定义为国际 p210 转录本上 BCR-ABL1 转录本≤0.1%，p190 转录本从基线降低 3 对数级。深度分子缓解（DMR）定义为无法定量检测到 BCR-ABL1 转录本，灵敏度为 0.01%。分子复发定义为 MMR 丢失。无治疗缓解（TFR）定义为从 TKI 停药至分子复发、末次随访或任何原因死亡的时间。
在停用 TKI 时，6 例患者的转录本水平无法检测到，2 例患者<0.01%，另 1 例患者为 0.01%。在停用 TKI 之前，TKI 治疗和 DMR 的中位时间分别为 70 个月和 47 个月。未发生形态学复发。3 例患者（33%）在中位时间 6 个月时发生分子复发。所有 3 例患者均恢复 TKI 治疗，其中 2 例在中位时间 13 个月后恢复 DMR。中位随访 49 个月后，中位 TFR 尚未达到，4 年 TFR 率为 65%。有分子复发和无分子复发患者的 DMR 中位时间分别为 22 个月和 58 个月（p=0.096）。
在毒性强烈的情况下，在 Ph 阳性 ALL 患者中停用 HSCT 之外的 TKI 可能仅适用于那些深度和长期 DMR 并接受密切和频繁监测的高度选择患者群体。非常需要在前瞻性临床试验中验证这些发现。
