Alexandra Bazeos

Adherence Is the Critical Factor for Achieving Molecular Responses in Patients With Chronic Myeloid Leukemia Who Achieve Complete Cytogenetic Responses on Imatinib

PURPOSE There is a considerable variability in the level of molecular responses achieved with imatinib therapy in patients with chronic myeloid leukemia (CML). These differences could result from variable therapy adherence. METHODS Eighty-seven patients with chronic-phase CML treated with imatinib 400 mg/d for a median of 59.7 months (range, 25 to 104 months) who had achieved complete cytogenetic response had adherence monitored during a 3-month period by using a microelectronic monitoring device. Adherence was correlated with levels of molecular response. Other factors that could influence outcome were also analyzed. RESULTS Median adherence rate was 98% (range, 24% to 104%). Twenty-three patients (26.4%) had adherence <or= 90%; in 12 of these patients (14%), adherence was <or= 80%. There was a strong correlation between adherence rate (<or= 90% or > 90%) and the 6-year probability of a 3-log reduction (also known as major molecular response [MMR]) in BCR-ABL1 transcripts (28.4% v 94.5%; P < .001) and also complete molecular response (CMR; 0% v 43.8%; P = .002). Multivariate analysis identified adherence (relative risk [RR], 11.7; P = .001) and expression of the molecular human organic cation transporter-1 (RR, 1.79; P = .038) as the only independent predictors for MMR. Adherence was the only independent predictor for CMR. No molecular responses were observed when adherence was <or= 80% (P < .001). Patients whose imatinib doses were increased had poor adherence (86.4%). In this latter population, adherence was the only independent predictor for inability to achieve an MMR (RR, 17.66; P = .006). CONCLUSION In patients with CML treated with imatinib for some years, poor adherence may be the predominant reason for inability to obtain adequate molecular responses.

hOCT1 transcript levels and single nucleotide polymorphisms as predictive factors for response to imatinib in chronic myeloid leukemia

hOCT1 transcript levels and single nucleotide polymorphisms as predictive factors for response to imatinib in chronic myeloid leukemia

Tyrosine kinase inhibitors impair B-cell immune responses in CML through off-target inhibition of kinases important for cell signaling

Tyrosine kinase inhibitors (TKIs) have significant off-target multikinase inhibitory effects. We aimed to study the impact of TKIs on the in vivo B-cell response to vaccination. Cellular and humoral responses to influenza and pneumococcal vaccines were evaluated in 51 chronic phase chronic myeloid leukemia (CML) patients on imatinib, or second-line dasatinib and nilotinib, and 24 controls. Following vaccination, CML patients on TKI had significant impairment of IgM humoral response to pneumococcus compared with controls (IgM titer 79.0 vs 200 U/mL, P = .0006), associated with significantly lower frequencies of peripheral blood IgM memory B cells. To elucidate whether CML itself or treatment with TKI was responsible for the impaired humoral response, we assessed memory B-cell subsets in paired samples collected before and after imatinib therapy. Treatment with imatinib was associated with significant reductions in IgM memory B cells. In vitro coincubation of B cells with plasma from CML patients on TKI or with imatinib, dasatinib, or nilotinib induced significant and dose-dependent inhibition of Brutons tyrosine kinase and indirectly its downstream substrate, phospholipase-C-γ2, both important in B-cell signaling and survival. These data indicate that TKIs, through off-target inhibition of kinases important in B-cell signaling, reduce memory B-cell frequencies and induce significant impairment of B-cell responses in CML.

Current pre-clinical and clinical advances in the BCR-ABL1-positive and -negative chronic myeloproliferative neoplasms

Though it has been remarkable to have witnessed the major advances in the understanding of the molecular pathogenesis of the chronic myeloproliferative neoplasms (MPN) over the past three decades, many challenges remain. The advances began with the identification of the BCR-ABL1 gene in chronic myeloid leukemia (CML) in 1985, leading to the introduction of ABL1 tyrosine kinase inhibitors (TKIs), and the JAK2V617F mutation in polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) in 2005, leading to the JAK inhibitors.1–3 CML is now arguably the most successfully treated human malignancy. Despite these remarkable achievements, the quest for cure, functionally defined as treatment-free remission after discontinuation of TKI therapy, remains difficult.4 In the BCR-ABL1 negative MPNs, a similar degree of success has not been achieved, perhaps because of the rather surprising clonal complexity of these disorders and the increasing molecular evidence of the need for JAK2V617F mutation to cooperate with other genetic aberrations in the initiation and progression of the disease. This clonal complexity needs to be elucidated further in order to recognize clinically relevant candidate therapeutic targets. Herein, we review some of the topical challenges and successes in the biology and therapy of the MPNs that were discussed at the 7th post-American Society of Hematology CML-MPN workshop, which took place in Atlanta on December 11–12, 2012, and up-dated prior to this publication.