Pacelli Paola, Santoni Adele, Sicuranza Anna, Abruzzese Elisabetta, Giai Valentina, Crugnola Monica, Annunziata Mario, Galimberti Sara, Iurlo Alessandra, Luciano Luigiana, Sorà Federica, Fava Carmen, Bestoso Elena, Marzano Cristina, Cartocci Alessandra, Defina Marzia, Sammartano Vincenzo, Cencini Emanuele, Raspadori Donatella, Bocchia Monica
Hematology Unit, University of Siena, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Sant'Eugenio Hospital, Tor Vergata University, Rome, Italy.
Front Pharmacol. 2023 May 26;14:1194712. doi: 10.3389/fphar.2023.1194712. eCollection 2023.
In chronic myeloid leukemia (CML), about half of the patients achieving a deep and stable molecular response with tyrosine kinase inhibitors (TKIs) may discontinue TKI treatment without disease recurrence. As such, treatment-free remission (TFR) has become an ambitious goal of treatment. Given the evidence that deepness and duration of molecular response are necessary but not sufficient requisites for a successful TFR, additional biological criteria are needed to identify CML patients suitable for efficacious discontinuation. Leukemia stem cells (LSCs) are supposed to be the reservoir of the disease. Previously, we demonstrated that residual circulating CD34+/CD38-/CD26+ LSCs were still detectable in a consistent number of CML patients during TFR. CML LSCs could be easily identified by flow-cytometry as they express the CD34+/CD38-/CD26+ phenotype. In this study, we explored the role of these cells and their correlation with molecular response in a cohort of 109 consecutive chronic phase CML patients prospectively monitored from the time of TKI discontinuation. After a median observation time of 33 months from TKI discontinuation, 38/109 (35%) patients failed TFR after a median time of 4 months, while 71/109 (65%) patients are still in TFR. At TKI discontinuation, peripheral blood CD26+LSCs were undetectable in 48/109 (44%) patients and detectable in 61/109 (56%). No statistically significant correlation between detectable/undetectable CD26+LSCs and the rate of TFR loss was found ( = 0.616). The incidence of TFR loss based on the type of TKI treatment was statistically significant for imatinib treatment compared to that of nilotinib ( = 0.039). Exploring the behavior of CD26+LSCs during TFR, we observed fluctuating values that were very variable between patients, and they were not predictive of TFR loss. Up to date, our results confirm that CD26+LSCs are detectable at the time of TKI discontinuation and during TFR. Moreover, at least for the observation median time of the study, the persistence of "fluctuating" values of residual CD26+LSCs does not hamper the possibility to maintain a stable TFR. On the contrary, even patients discontinuing TKI with undetectable CD26+LSCs could undergo TFR loss. Our results suggest that factors other than residual LSCs "burden" playing an active role in controlling disease recurrence. Additional studies evaluating CD26+LSCs' ability to modulate the immune system and their interaction in CML patients with very long stable TFR are ongoing.
在慢性髓性白血病（CML）中，约一半使用酪氨酸激酶抑制剂（TKIs）获得深度且稳定分子反应的患者可能停用TKI治疗而无疾病复发。因此，无治疗缓解（TFR）已成为一个雄心勃勃的治疗目标。鉴于分子反应的深度和持续时间是成功实现TFR的必要但不充分条件，需要额外的生物学标准来识别适合有效停药的CML患者。白血病干细胞（LSCs）被认为是该疾病的根源。此前，我们证明在TFR期间，仍有相当数量的CML患者可检测到残留的循环CD34⁺/CD38⁻/CD26⁺ LSCs。CML LSCs可通过流式细胞术轻松识别，因为它们表达CD34⁺/CD38⁻/CD26⁺表型。在本研究中，我们在一组从停用TKI开始就进行前瞻性监测的109例连续慢性期CML患者中，探讨了这些细胞的作用及其与分子反应的相关性。从停用TKI起经过33个月的中位观察时间后，109例患者中有38例（35%）在中位4个月时TFR失败，而71例（65%）患者仍处于TFR状态。在停用TKI时，109例患者中有48例（44%）外周血CD26⁺ LSCs检测不到，61例（56%）可检测到。未发现可检测到/未检测到的CD26⁺ LSCs与TFR丧失率之间存在统计学显著相关性（P = 0.616）。与尼洛替尼相比，基于TKI治疗类型的TFR丧失发生率在伊马替尼治疗中具有统计学显著性（P = 0.039）。在探索TFR期间CD26⁺ LSCs的行为时，我们观察到其值波动，患者之间差异很大，且它们不能预测TFR丧失。迄今为止，我们的结果证实，在停用TKI时及TFR期间可检测到CD26⁺ LSCs。此外，至少在本研究的中位观察时间内，残留CD26⁺ LSCs“波动”值的持续存在并不妨碍维持稳定TFR的可能性。相反，即使停用TKI时CD26⁺ LSCs检测不到的患者也可能出现TFR丧失。我们的结果表明，除了残留LSCs“负荷”之外，还有其他因素在控制疾病复发中发挥积极作用。正在进行额外的研究，评估CD26⁺ LSCs调节免疫系统的能力及其在具有非常长稳定TFR的CML患者中的相互作用。
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