Allografting for Bosutinib, Imatinib, Nilotinib, Dasatinib, and Interferon Resistant Chronic Myeloid Leukemia without ABL Kinase Mutation

Abstract

The current treatment of chronic phase chronic myeloid leukemia (CML) consists of oral tyrosine kinase inhibitors (TKIs). However, high-risk CML may present with an aggressive course which may result in blastic crisis or a “difficult-to-manage” state with available treatments. The aim of this paper is to report a patient with complicated CML resistant to treatment and progressed despite the administration of bosutinib, imatinib mesylate, nilotinib, dasatinib, interferon alpha 2a, cytotoxic chemotherapy, and allogeneic hematopoietic stem cell transplantation. The striking point of this case story is that no Abl kinase domain mutation against TKIs has been detected during this very complicated disease course of CML. Meanwhile, challenging cases will always be present despite the hope and progress in CML in the TKI era.

Drug Therapy in the Progressed CML Patient With Multi-Tki Failure

“…The timing of alloSCT has changed to third- or fourth-line CML after failure of the second-generation TKIs. 2 , 6 The definition of transplant eligibility is never absolute since it is based on the balance between the disease risk of CML and the mortality/morbidity risk of alloSCT. 5…”

Who 2016 Definition of Chronic Myeloid Leukemia and Tyrosine Kinase Inhibitors

“…Ponatinib is the only TKI for T315I before HSCT. The most challenging situations in patients with CML are resistance to all available TKIs in patients who inability to undergo transplantation, or recurrence after HSCT, especially into blastic crisis [26]. The fourth-generation drug asciminib, a specific TKI targeting the BCR-ABL1 myristoyl-binding site, an allosteric regulatory domain, and PF-114 mesylate [27], have the potential to treat patients with resistance to ATP-binding-site TKIs, including T315I [28,29].…”

Current Management of Chronic Myeloid Leukemia with Tyrosine Kinase Inhibitors

“…Likewise, the molecular responses of MR4 or MR4.5 could lead to the discontinuation of the drug with proper molecular monitoring (TFR; treatment-free remission) within the context of clinical trials [ 18 ]. On the other hand, disease progression (accelerated phase (AP) CML or blastic crisis (BC)) under TKI is a great disaster [ 19 , 20 , 21 ]. Survival after progression into AP/BC is still significantly shorter, even in the TKI era.…”

“…Pregnancy represents a cause for TKI discontinuation because of the negative impact of any TKI on organogenesis. Patients with AP/BC CML should be treated with the most powerful TKI available and multi-agent chemotherapy before allografting [ 19 , 20 , 21 , 65 , 69 , 70 , 71 ]. Since those patients with advanced-phase CML still do have a worse prognosis, prevention of disease progression is the most significant aspect of CML disease management.…”