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What does a deep molecular response signify?

Tyrosine kinase inhibitor (TKI) treatment for patients with chronic myeloid leukemia (CML) has dramatically improved longerterm outcomes through achievement of deep cytogenetic responses in the majority of patient cases and provided compelling clinical evidence for so-called oncogene addiction, whereby cancer cells demonstrate exquisite reliance on the continued activity of a particular protein for survival. This success story is further underscored by results from imatinib discontinuation studies, which have demonstrated that approximately 40% of patients who achieve a stable ( 2 years) 4.5-log reduction in breakpoint cluster region (BCR) –ABL transcript (MR) remain in molecular remission several years after discontinuing TKIs. In the article accompanying ours, Hehlmann et al report that with longer-term (approximately 9 years) follow-up, 70% of patients treated with imatinib achieved MR, and these responses were more common in patients who received higher doses of imatinib through a tolerability-adapted strategy. If these deep molecular responses are generally durable ( 2 years), one may expect that a substantial proportion of patients with CML will eventually be able to discontinue treatment for several years without suffering molecular relapse. Previous studies have suggested that deeper remissions are generally associated with superior outcomes; however, this is the first study to our knowledge to demonstrate that achievement of a deep molecular response (ie, MR) predicts statistically significant superior survival relative to that in patients with only a 2-log reduction in BCR-ABL transcript level (ie, MR), which has been suggested to be the minimal molecular response equivalent of a complete cytogenetic response (CCR). The fact that these results were achieved with imatinib has important economic implications in light of its patent expiration in 2015. The Philadelphia chromosome translocation that is the hallmark of CML fuses ABL (non–receptor tyrosine kinase–encoding gene) to the BCR gene, giving rise to the chimeric BCR-ABL kinase. In the process, the segment of ABL responsible for autoinhibition is lost. Additionally, BCR-mediated oligomerization of the fusion kinase leads to transphosphorylation and BCR-ABL activation, resulting in cell-cycle progression, proliferation, antiapoptotic signals, and gene transcription modulation (Fig 1). Phosphorylation of BCR-ABL at Tyr-177 allows formation of a complex between GRB2, GAB2, and SOS, which activates RAS, leading to cell proliferation through the mitogen-activated protein kinase (MAPK) pathway. RAS also activates the phosphoinositide 3-kinase (PI3K)/AKT pathway, resulting in promotion of proteosomal degradation of p27, a protein involved in maintaining G1-phase arrest; suppression of the FOXO transcription factors, which are involved in tumor suppression mechanisms and cell-cycle quiescence; and activation of mammalian target of rapamycin (mTOR), a serine/threonine kinase with multiple functions that stimulates cell survival and cell growth, enhances protein translation, and negatively regulates the cellular process of autophagy, which recycles intracellular components and facilitates survival in conditions of stress. Signal transducer and activator of transcription 5 (STAT5) activation has been demonstrated to be indispensable for leukemic cell survival. In CML cells, activation of STAT5 seems to occur independently of the canonical Janus kinase 2 (JAK2)/STAT5 pathway, and evidence for direct activation by BCR-ABL in vitro has been provided. Activated STAT5 promotes the transcription of genes that lead to cytokineindependent growth and evasion of apoptosis. Previous studies have demonstrated that CML cell lines require continued activation of at least two of the three canonical BCR-ABL– activated pathways (STAT5, PI3K/AKT, and RAS/MAPK) for survival. On binding to the ABL kinase domain, imatinib prevents ATP binding and hydrolysis, effecting apoptosis in BCR-ABL–dependent CML cells via loss of signaling through these pathways, although how BCR-ABL rewires cellular signaling to create a dependence on its activity is not clear. Mutations in the BCR-ABL kinase domain, which alter drug-binding capacity, are the most common cause of TKI resistance. This observation led to the development of the secondgeneration TKIs dasatinib, nilotinib, and bosutinib, which are notably more potent than imatinib and seem to effect deeper and faster molecular remissions than standard-dose imatinib. However, these drugs are ineffective against the BCR-ABL/T315I mutant, for which ponatinib, a pan–BCR-ABL third-generation TKI, represents the most promising treatment. Amplification of the BCR-ABL gene is a less common mechanism of imatinib resistance, which presumably leads to resistance through accumulation of increased levels of BCRABL capable of escaping the intracellular drug concentrations achieved by standard-dose imatinib. This mechanism, identified as the most frequent cause of resistance in CML cell lines, has also been observed in patients with blast-phase CML, although it seems to be uncommon in patients with chronic-phase disease. Why might higher doses of imatinib (and more-potent BCRABL TKIs) achieve faster and deeper molecular response rates, as reported by Hehlmann et al? One possible explanation is that standard-dose imatinib provides suboptimal BCR-ABL inhibition in some patients, resulting in maintenance of prosurvival signaling or allowing sufficient time for cell rewiring and avoidance of apoptosis, JOURNAL OF CLINICAL ONCOLOGY U N D E R S T A N D I N G T H E P A T H W A Y VOLUME 32 NUMBER 5 FEBRUARY 1