Do we need more drugs for chronic myeloid leukemia?

Abstract

The introduction of protein tyrosine kinase inhibitors (TKIs) in 1998 transformed the management of chronic myeloid leukemia (CML), leading to significantly reduced mortality and improved 5 year survival rates. However, the CML community is faced with several clinical issues that need to be addressed. Ten to 15% of CML patients are diagnosed in advanced phase, and small numbers of chronic phase (CP) cases experience disease progression each year during treatment. For these patients, TKIs induce only transient responses and alternative treatment strategies are urgently required. Depending on choice of first line TKI, approximately 30% of CML CP cases show suboptimal responses, due to a combination of poor compliance, drug intolerance, and drug resistance, with approximately 50% of TKI-resistance caused by kinase domain mutations and the remainder due to unknown mechanisms. Finally, the chance of successful treatment discontinuation is on the order of only 10-20% related to disease persistence. Disease persistence is a poorly understood phenomenon; all CML patients have functional Philadelphia positive (Ph+) stem and progenitor cells in their bone marrows and continue to express BCR-ABL1 by DNA PCR, even when in very deep remission and following treatment discontinuation. What controls the maintenance of these persisting cells, whether it is necessary to fully eradicate the malignant clone to achieve cure, and how that might be approached therapeutically are open questions.

Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study

“…[42][43][44] Here, analysis of baseline parameters allowed us to demonstrate that patients with a history of suboptimal response or TKI resistance had a significantly higher incidence of molecular relapse than did newly diagnosed patients and those with prior intolerance to imatinib. This result is corroborated by research from the DADI trial, in which discontinuation of second-line or subsequent dasatinib was proposed for CP-CML patients with deep molecular response (BCR-ABL1 IS , 0.0069%) for at least 1 year.…”

Differentiation status of primary chronic myeloid leukemia cells affects sensitivity to BCR-ABL1 inhibitors

“…However, not all patients respond optimally to TKIs and some develop intolerance or secondary resistance. Most cases of TKI resistance are caused by mutations in the kinase domain of the BCR-ABL1 gene, but some patients develop resistance due to other mechanisms [3, 4]. Although third generation TKIs targeting key gatekeeper mutations have been developed (e.g.…”

Twisting IL-1 signaling to kill CML stem cells

“…The therapeutic relevance of such studies rests on the fact that a successful CML eradication therapy will not only prevent disease relapse upon TKI discontinuation but also release the majority of patients from life-long and economically challenging TKI therapy and, perhaps, will positively impact prognosis of those patients who become resistant to multiple TKIs and/or undergo blastic transformation. 3 …”