Advances in the treatment of chronic myeloid leukemia

Although imatinib is firmly established as an effective therapy for newly diagnosed patients with chronic myeloid leukemia (CML), the field continues to advance on several fronts. In this minireview we cover recent results of second generation tyrosine kinase inhibitors in newly diagnosed patients, investigate the state of strategies to discontinue therapy and report on new small molecule inhibitors to tackle resistant disease, focusing on agents that target the T315I mutant of BCR-ABL. As a result of these advances, standard of care in frontline therapy has started to gravitate toward dasatinib and nilotinib, although more observation is needed to fully support this. Stopping therapy altogether remains a matter of clinical trials, and more must be learned about the mechanisms underlying the persistence of leukemic cells with treatment. However, there is good news for patients with the T315I mutation, as effective drugs such as ponatinib are on their way to regulatory approval. Despite these promising data, accelerated or blastic phase disease remains a challenge, possibly due to BCR-ABL-independent resistance

Genomic Abnormalities as Biomarkers and Therapeutic Targets in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a highly heterogeneous malignancy characterized by the clonal expansion of myeloid stem and progenitor cells in the bone marrow, peripheral blood, and other tissues. AML results from the acquisition of gene mutations or chromosomal abnormalities that induce proliferation or block differentiation of hematopoietic progenitors. A combination of cytogenetic profiling and gene mutation analyses are essential for the proper diagnosis, classification, prognosis, and treatment of AML. In the present review, we provide a summary of genomic abnormalities in AML that have emerged as both markers of disease and therapeutic targets. We discuss the abnormalities of RARA, FLT3, BCL2, IDH1, and IDH2, their significance as therapeutic targets in AML, and how various mechanisms cause resistance to the currently FDA-approved inhibitors. We also discuss the limitations of current genomic approaches for producing a comprehensive picture of the activated signaling pathways at diagnosis or at relapse in AML patients, and how innovative technologies combining genomic and functional methods will improve the discovery of novel therapeutic targets in AML. The ultimate goal is to optimize a personalized medicine approach for AML patients and possibly those with other types of cancers

Figures S1 - S4 and Table S1 from Alginate foam-based three-dimensional culture to investigate drug sensitivity in primary leukaemia cells

Figure S1: (a) The process of producing microbubbles using a microfluidic V-junction. (b) Optical micrograph of the alginate microbubbles collected in calcium chloride and their changes during time laps immediately after collection (zero time).; Figure S2: The relative proliferation of primary leukaemia cells from AML patients (n=3) in foam-based scaffold (3D) compared to 2D is shown. The experiment was done in triplicate and shows higher proliferation of the cells in (3D) compared to 2D culture (p value: 0.005).; Figure S3: Enhanced myelomonocytic differentiation of blasts from an AML patient in 3D compared to 2D culture. The myeloblasts were further depleted (down to 50%) in CD34+ marker (red dots) after 3 days of culture in 3D compared to 2D.; Table S1: This table shows the percentage for various myeloid markers at day 0 and at 72 hours in 2D and 3D cultures for the samples shown in figure 3.; Figure S4: This figure shows the statistical differences between 2D and 3D cultures at 72 hours for the patients from figure 3

Serial measurement of BCR-ABL transcripts in the peripheral blood after allogeneic stem cell transplant for chronic myeloid leukemia: an attempt to define patients who may not require further therapy

We identified 243 patients with Ph-positive CML who had BCR-ABL transcripts monitored by quantitative RT-PCR after allogeneic stem cell transplant for a median of 84.3 months. Individual patients were regarded as having achieved molecular relapse (MR) if the BCR-ABL/ABL ratio exceeded 0.02% on three occasions or reached 0.05% on two occasions. Patients were allocated to one of four categories: (1) 36 patients were 'persistently negative' or had a single low level positive result, (2) 51 patients, 'fluctuating positive, low level', had more than one positive result but never more than two consecutive positive results; (3) 27 patients, 'persistently positive, low level', had persisting low levels of BCR-ABL transcripts but never more than three consecutive positive results, and (4) 129 patients relapsed. In 107 of these relapse was based initially only on molecular criteria; in 72 (67.3%) patients the leukemia progressed to cytogenetic or hematologic relapse either prior to or during treatment with donor lymphocyte infusions. We conclude that the pattern of BCR-ABL transcript levels after allograft is variable; only a minority of patients with fluctuating or persistent low levels of BCR-ABL transcript satisfied our definitions of MR whereas the majority of patients who did so were likely to progress further