Bosutinib, a Lyn/Btk inhibiting tyrosine kinase inhibitor, is ineffective in advanced systemic mastocytosis

Abstract

a trend was seen for improved survival (P 5 0.08).Our goal is to improve the nationwide survival of myeloma patients. We have established a national registry of all myeloma patients to identify areas of intervention. A population-based survey showed no difference in causes of death among patients ineligible for HDT, who died within 30 days from diagnosis as compared to patients who died between 31 and 180 days. Patients who died within 30 days had higher LDH levels and lower levels of plasma albumin as compared to those patients who died within 31-180 days, and may reflect patients with high tumor burden and a high degree of stress caused by severe infection, impaired kidney, and liver function. When compared with patients who died later than 180 days of diagnosis, WHO performance status was worse in patients with early death. A clinician will not find these results surprising. However, our data may imply that elderly patients with multiple myeloma are diagnosed with delay and a nationwide focus is now on accelerated diagnosis to clarify whether individuals presenting with an M-protein in blood or urine or with myeloma associated symptoms are suffering from myeloma. Furthermore, our survey showed that among patients with early deaths the most common causes of deaths were infections, cardiovascular failure, and renal failure. Standard induction treatment for patients ineligible for HDT now includes adjustment of chemotherapy dose according to co-morbidity and a proteasome inhibitor.Clinicians use several approaches to avoid life-threatening infections among the elderly such as granulocyte colony-stimulating factor (G-CSF) in patients with neutropenia and supportive treatment with immunoglobulins. To provide the patients with the best antibiotic treatment in future we are now conducting a nationwide prospective study on prophylactic antibiotic treatment.

Consensus Opinion on Allogeneic Hematopoietic Cell Transplantation in Advanced Systemic Mastocytosis

“…Given that approximately 90% of patients with advanced SM have a mutation in the KIT gene (mostly KIT D816V), tyrosine kinase inhibitors (TKI) have also been used recently; however, the clinical efficacy of most KIT-targeted TKIs has been disappointing. The KIT D816V mutation is resistant to imatinib, and despite in vitro activity against KIT D816V, dasatinib and nilotinib have shown limited activity in phase II trials in KIT D816V-mutated advanced SM [12][13][14][15][16][17][18]. Midostaurin, a multikinase inhibitor available on an investigational and compassionate-use basis, has shown promising results in patients with advanced SM in a phase II study [19].…”

Advanced systemic mastocytosis: from molecular and genetic progress to clinical practice

“…49 However, bosutinib is unable to induce any response in patients with AdvSM. 87 Treatment in advanced SM haematologica | 2016; 101 (10) 1137 Figure 2. Synthesis of the frequency of the various molecular defects found in AdvSM, which sums up all the advanced (AdvSM) SM patients (n=122) reported in the studies by Tefferi et al, 62 Wilson et al, 63 Traina et al, 61 Schwaab et al 64 and Hanssens et al 65 The frequency (%) of cases found positive for each genetic defect is represented in red, whereas the frequency of patients for whom the corresponding defect was not tested is represented in blue.…”

SRC-Family Kinases in Acute Myeloid Leukaemia and Mastocytosis

“…This observation positioned SFKs as attractive targets for the treatment of systemic mastocytosis. However, selective inhibition of the activity of SFKs alone, using an inhibitor such as bosutinib, has been shown to be ineffective as a stand-alone agent; their use in combination therapy may prove to be more valuable [ 111 ].…”