Targeting leukemic stem cells in chronic myeloid leukemia: Is it worth the effort?

Chronic myeloid leukemia (CML) is a classical example of stem cell cancer since it arises in a multipotent hematopoietic stem cell upon the acquisition of the t(9;22) chromosomal transloca-tion, that converts it into a leukemic stem cell (LSC). The resulting BCR‐ABL1 fusion gene encodes a deregulated tyrosine kinase that is recognized as the disease driver. Therapy with tyrosine kinase inhibitors (TKIs) eliminates progenitor and more differentiated cells but fails to eradicate quiescent LSCs. Thus, although many patients obtain excellent responses and a proportion of them can even attempt treatment discontinuation (treatment free remission [TFR]) after some years of therapy, LSCs persist, and represent a potentially dangerous reservoir feeding relapse and hampering TFR. Over the past two decades, intensive efforts have been devoted to the characterization of CML LSCs and to the dissection of the cell‐intrinsic and ‐extrinsic mechanisms sustaining their persistence, in an attempt to find druggable targets enabling LSC eradication. Here we provide an overview and an update on these mechanisms, focusing in particular on the most recent acquisitions. Moreover, we provide a critical appraisal of the clinical relevance and feasibility of LSC targeting in CML

Systemic mastocytosis: Molecular landscape and implications for treatment

Over the past decade, we have witnessed significant advances in the molecular characterization of systemic mastocytosis (SM). This has provided important information for a better understanding of the pathogenesis of the disease but has also practically impacted the way we diagnose and manage it. Advances in molecular testing have run in parallel with advances in therapeutic targeting of constitutive active KIT, the major driver of the disease. Therefore, assessing the molecular landscape in each SM patient is essential for diagnosis, prognosis, treatment, and therapeutic efficacy monitoring. This is facilitated by the routine availability of novel technologies like digital PCR and NGS. This review aims to summarize the pathogenesis of the disease, discuss the value of molecular diagnostic testing and how it should be performed, and provide an overview of present and future therapeutic concepts based on fine molecular characterization of SM patients

Current treatment approaches in CML.

Take home messages Five tyrosine kinase inhibitors are available, the treatment strategy is still challenging. Baseline risk, comorbidities, and patient and physician expectations play a pivotal role. Treatment-free remission is a new opportunity

BCR-ABL1 mutation development during first-line treatment with dasatinib or imatinib for chronic myeloid leukemia in chronic phase

BCR-ABL1 mutations are a common, well-characterized mechanism of resistance to imatinib as first-line treatment of chronic myeloid leukemia in chronic phase (CML-CP). Less is known about mutation development during first-line treatment with dasatinib and nilotinib, despite increased use because of higher response rates compared with imatinib. Retrospective analyses were conducted to characterize mutation development in patients with newly diagnosed CML-CP treated with dasatinib (n=259) or imatinib (n=260) in DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML-CP), with 3-year minimum follow-up. Mutation screening, including patients who discontinued treatment and patients who had a clinically relevant on-treatment event (no confirmed complete cytogenetic response (cCCyR) and no major molecular response (MMR) within 12 months; fivefold increase in BCR-ABL1 with loss of MMR; loss of CCyR), yielded a small number of patients with mutations (dasatinib, n=17; imatinib, n=18). Dasatinib patients had a narrower spectrum of mutations (4 vs 12 sites for dasatinib vs imatinib), fewer phosphate-binding loop mutations (1 vs 9 mutations), fewer multiple mutations (1 vs 6 patients) and greater occurrence of T315I (11 vs 0 patients). This trial was registered at www.clinicaltrials.gov as NCT00481247.T P Hughes, G Saglio, A Quintás-Cardama, M J Mauro, D-W Kim, J H Lipton6, M B Bradley-Garelik, J Ukropec and A Hochhau

Nilotinib: a novel encouraging therapeutic option for chronic myeloid leukemia patients with imatinib resistance or intolerance

Although high rates of complete hematologic and cytogenetic remission have been observed in patients with chronic phase chronic myeloid leukemia (CML) treated with imatinib, a short duration of response with eventual emergence of imatinib resistance has also been reported in a subset of CML patients. The most frequent clinically relevant mechanisms that change imatinib sensitivity in BCR-ABL-transformed cells are mutations within the Abl kinase domain, affecting several of its properties. Crystal structure analysis of the Abl-imatinib complex has proven helpful in identifying potential critical residues that hinder interactions of imatinib with mutated Abl. This has led to the development of a second generation of targeted therapies such as nilotinib and dasatinib, already in phase II clinical trials or SKI-606 and MK-0457 in phase I trials. In this review, we discuss the activity of nilotinib, developed by Novartis using a rational drug design strategy in which imatinib served as the lead compound. Preliminary studies demonstrated that nilotinib has more efficacy than imatinib in inhibiting proliferation of BCR-ABL-dependent cells, a relatively safety profile and clinical efficacy in all phases of CML

Gut microbiome response to a modern Paleolithic diet in a Western lifestyle context

The modern Paleolithic diet (MPD), featured by the consumption of vegetables, fruit, nuts, seeds, eggs, fish and lean meat, while excluding grains, dairy products, salt and refined sugar, has gained substantial public attention in recent years because of its potential multiple health benefits. However, to date little is known about the actual impact of this dietary pattern on the gut microbiome (GM) and its implications for human health. In the current scenario where Western diets, low in fiber while rich in industrialized and processed foods, are considered one of the leading causes of maladaptive GM changes along human evolution, likely contributing to the increasing incidence of chronic non-communicable diseases, we hypothesize that the MPD could modulate the Western GM towards a more “ancestral” configuration. In an attempt to shed light on this, here we profiled the GM structure of urban Italian subjects adhering to the MPD, and compared data with other urban Italians following a Mediterranean Diet (MD), as well as worldwide traditional hunter-gatherer populations from previous publications. Notwithstanding a strong geography effect on the GM structure, our results show an unexpectedly high degree of biodiversity in MPD subjects, which well approximates that of traditional populations. The GM of MPD individuals also shows some peculiarities, including a high relative abundance of bile-tolerant and fat-loving microorganisms. The consumption of plant-based foods–albeit with the exclusion of grains and pulses–along with the minimization of the intake of processed foods, both hallmarks of the MPD, could therefore contribute to partially rewild the GM but caution should be taken in adhering to this dietary pattern in the long term

Assessing Measurable Residual Disease in Chronic Myeloid Leukemia. BCR-ABL1 IS in the Avant-Garde of Molecular Hematology

Chronic myelogenous leukemia (CML) is a malignancy of the myeloid cell lineage characterized by a recurrent chromosomal abnormality: the Philadelphia chromosome, which results from the reciprocal translocation of the chromosomes 9 and 22. The Philadelphia chromosome contains a fusion gene called BCR-ABL1. The BCR-ABL1 codes for an aberrantly functioning tyrosine kinase that drives the malignant proliferation of the founding clone. The advent of tyrosine kinase inhibitors (TKI) represents a landmark in the treatment of CML, that has led to tremendous improvement in the remission and survival rates. Since the introduction of imatinib, the first TKI, several other TKI have been approved that further broadened the arsenal against CML. Patients treated with TKIs require sensitive monitoring of BCR-ABL1 transcripts with quantitative real-time polymerase chain reaction (qRT-PCT), which has become an essential part of managing patients with CML. In this review, we discuss the importance of the BCR-ABL1 assay, and we highlight the growing importance of BCR-ABL1 dynamics. We also introduce a mathematical correction for the BCR-ABL1 assay that could help homogenizing the use of the ABL1 as a control gene. Finally, we discuss the growing body of evidence concerning treatment-free remission. Along with the continuous improvement in the therapeutic arsenal against CML, the molecular monitoring of CML represents the avant-garde in the struggle to make CML a curable disease

Management of imatinib-resistant CML patients

Imatinib has had marked impact on outcomes in chronic myelogenous leukemia (CML) patients for all stages of the disease and is endorsed by international treatment guidelines as the first line option. Although imatinib is highly effective and well tolerated, the development of resistance represents a clinical challenge. Since the most frequently identified mechanism of acquired imatinib resistance is bcr-abl kinase domain point mutations, periodic hematologic, cytogenetic, and molecular monitoring is critical throughout imatinib therapy. Once cytogenetic remission is achieved, residual disease can be monitored by bcr-abl transcript levels as assayed by reverse transcription polymerase chain reaction (RT-PCR). Detection of bcr-abl mutants prior to and during imatinib therapy can aid in risk stratification as well as in determining therapeutic strategies. Thus, mutation screening is indicated in patients lacking or losing hematologic response. Moreover, search for mutations should also be performed when a 3-log reduction of bcr-abl transcripts is not achieved or there is a reproducible increase of transcript levels. In patients harboring mutations which confer imatinib resistance, novel second line tyrosine kinase inhibitors have demonstrated encouraging efficacy with low toxicity. Only the T315I bcr-abl mutant has proved totally resistant to all clinically available bcr-abl inhibitors. Strategies to further increase the rates of complete molecular remissions represent the next frontier in the targeted therapy of CML patients