Leukemic Stem Cell Quantification in Newly Diagnosed Patients With Chronic Myeloid Leukemia Predicts Response to Nilotinib Therapy

Abstract

Purpose: Leukemic stem cells (LSCs) may harbor important resistance to tyrosine kinase inhibitors in chronic myelogenous leukemia (CML). We identified Philadelphia chromosome (Ph)–positive CD34+CD38− bone marrow cells (here denoted LSCs) and addressed their response-predictive value in patients with CML (n = 48) subjected to nilotinib in the ENEST1st trial (NCT01061177). Experimental design: Two flow cytometry–based cell sorting methods were used with multiparameter-directed CD45- (MPFC) and BCR-ABL1 probe-linked (FISH) identification of Ph-positive cells, respectively. Results: We observed a positive correlation between the proportion of LSCs at diagnosis and established prognostic markers (blast count, spleen size, Sokal score, and hemoglobin). Conversely, a high LSC burden predicted for an inferior molecular response at 3 (MPFC and FISH), 6 (MPFC), 9 (FISH), and 15 months (FISH). During nilotinib therapy, the proportion of LSCs decreased rapidly. At 3 months, a median of only 0.3% LSCs remained among CD34+CD38− cells, and in 33% of the patients the LSC clone was not detectable anymore (FISH). The response kinetics was similar in LSC fractions as it was in the progenitor and unseparated bone marrow cell fractions. Conclusions: The proportion of LSCs at diagnosis, as analyzed by two independent methodologies, reflects the biology of the disease and appeared as a prognostic and response-predictive marker in patients with CML subjected to first-line nilotinib therapy. Clin Cancer Res; 22(16); 4030–8. ©2016 AACR.

Immunological monitoring of newly diagnosed CML patients treated with bosutinib or imatinib first-line

“…10 Therefore, it is also possible that imatinib has direct immunological effects in CML similarly as shown in gastrointestinal stromal tumors and neuroblastoma patients. 13,17,29 The initial fraction of leukemic stem cells at diagnosis is known to have an impact on the overall therapy outcome, 30,31 but also on the immune system, causing significant malfunction and suppression of the lymphocytes in CML patients. 28,[32][33][34] High Sokal risk CML patients have also been reported to have higher numbers of myeloid-derived suppressor and PD1expressing CD8 + T cells.…”

Pretreatment evaluation of fluorescence resonance energy transfer‐based drug sensitivity test for patients with chronic myelogenous leukemia treated with dasatinib

“…Recently, it was reported that leukemic stem cell quantification at diagnosis of CML is a strong predictive marker for molecular responses by imatinib, dasatinib and nilotinib. 28,29 In those studies, leukemic stem cell burden was correlated with other biological factors such as white blood cell count, blast percentage and spleen size. Moreover, patients with a low leukemic stem cell burden at diagnosis showed less hematological toxicity by the TKI and achieved higher rates of cytogenetic and molecular responses than did patients with a high leukemic stem cell burden.…”

Leukemia stem cell immunophenotyping tool for diagnostic, prognosis, and therapeutics

“…Their quiescent status is a key point as well, since it protects against drugs that target actively cycling cells, making them resistant to most available tyrosine kinase inhibitors (Deshpande et al, 2006;Thielen et al, 2016). Additionally, apoptosis entrance protection (de Figueiredo-Pontes et al, 2008) and aging avoidance (Kronenwett et al, 2005) have been described among other mechanisms to explain cell persistence and relapse occurrence (Bertrand et al, 2012;Blume et al, 2018;de Figueiredo-Pontes et al, 2008;Huang et al, 2015;Lainey et al, 2012;Picot et al, 2017;Qiu et al, 2014).…”

“…Again, disease is maintained by a reduced pool of LSCs that is also responsible for relapse. The chromosomal translocation target cell can be stem cells or multipotent progenitors (Thielen et al, 2016;Valent et al, 2014), but in both cases, the LSCs are quiescent, self-renewing, and chemotherapy-resistant (Thielen et al, 2016;Valent et al, 2014).…”

“…As discussed earlier, endosteal niche occupation is proposed to be one resistance mechanism (Zhi et al, ) that functions through the mechanical protection of chemotherapeutic drugs (Bertrand et al, ; Valent et al, ). Their quiescent status is a key point as well, since it protects against drugs that target actively cycling cells, making them resistant to most available tyrosine kinase inhibitors (Deshpande et al, ; Thielen et al, ). Additionally, apoptosis entrance protection (de Figueiredo‐Pontes et al, ) and aging avoidance (Kronenwett et al, ) have been described among other mechanisms to explain cell persistence and relapse occurrence (Bertrand et al, ; Blume et al, ; de Figueiredo‐Pontes et al, ; Huang et al, ; Lainey et al, ; Picot et al, ; Qiu et al, ).…”