Editorial

Greetings, and welcome to this issue of Therapeutic Advances in Hematology! This issue, like many before, contains a treasure-trove of data on basis of disease and therapeutics for blood cancers, and was a pleasure to read through. We, as always, appreciate the fine work of all the authors, and encourage the readership to consider submissions of your own.

This issue starts with an overview of epigenetic therapy from R. Popovic, M. Shah and J. Licht of Northwestern University in Chicago. They open up the discussion with an overview of the systems involved in regulation of gene expression, including DNA methylation, the ‘histone code’ and variable activation state of different genes, and the two targets exploited to date, namely DNA methyltransferase and histone deacetlyase inhibition. In addition to identification as targets, they acknowledge the recent discoveries of alterations in said targets and other related entities: DNMT3A mutation in AML/MDS; TET1 enzyme or TET1+ASXL1 in leukemia and myeloproliferative disorders; and mutations in IDH1 and IDH2, all with prognostic impact and/or pro-leukemogenic effects. Then they review both available therapies (DNMT and HDAC inhibitors) and emerging potential therapies based around abnormalities discovered in MLL (mixed lineage leukemia) rearranged leukemias. Lastly, they highlight the epigenetic regulators EZH2 and H3K27 and related enzymes and their effects in numerous cancers including lymphoma, myeloma, and leukemia, and their potential as therapeutic targets.

Next, we are treated to a helpful review of the iron chelator, deferasirox, and its use in patients with MDS and associated transfusion-related iron overload, by R. Adams and R. Bird, both from Princess Alexandra Hospital in Queensland, Australia. They open with an excellent overview of the pathogenesis of the process, an evaluation of a patient with iron overload, and how/when to decide that chelation is needed. This is followed by an in-depth summary of deferasirox and its mechanism of action, pharmacokinetics, and adverse event profile. They highlight GI effects and variable absorption, risk of hemorrhage, dermatologic and hepatic enzyme elevation, as well as renal effects and creatinine monitoring required, and avoiding rapid ‘de-ironing’. On the plus side, they highlight lack of infection risk, adjustable dose and efficacy, as well as improvement in hepatic and marrow function as a result and the preliminary observation of improved survival.

In the middle of this issue we find a manuscript near and dear to my area of work, namely a review of managing imatinib resistance from P. Bhamidipati and others from the Leukemia department at MD Anderson Cancer Center in Houston, TX. The authors strategically tackle the key elements of CML care in 2013, starting with understanding imatinib resistance and details within, such as the 315-position mutation and division between bcr-abl dependent and independent mechanisms, including the problem of lower rates of adherence with chronic therapy. They next review guidelines for how and when to monitor, built on a platform of treatment response expectations set forth by US (NCCN) and international (ELN) groups. Three distinct ‘pitfalls’ are then clarified, namely intolerance to imatinib and how to declare and manage it; rising transcripts and proper response to this; and cytogenetic changes in Ph negative cells, argued to be a minor concern and not worthy of change in strategy. True to the title of the work, the authors then systematically review the alternatives currently available beyond standard imatinib, including higher dose imatinib, nilotinib, dasatinib, bosutinib, omacetaxine, stem cell transplant, and in a bit more detail, ponatinib, the novel ‘third generation’ kinase inhibitor. A primer on CML strategy in 2013!

We then turn to lymphoid malignancies with an update on the pathobiology of the oncogenic kinase NPM-ALK from R. Lai and R. Ingham of the University of Alberta, Edmonton, Canada. They review the nature of this well-studied gene fusion and resulting constitutively activated tyrosine kinase. They highlight key downstream pathways such as STAT3 activation and elucidate additional key findings such as SHP1 silencing through methyltransferase interactions as well as constitutive activation of JAK3. Based on the JAK3 findings, the authors then sort through conflicting data on the role of cytokines in NPM-ALK lymphomagenesis. In addition to these, they note identification of beta-catenin activation, increased expression of HIF1-alpha and Twist1 and upregulation of Sox-2 as other relevant downstream effects. Further, the authors describe the role of mass spectrometry and identifying MSH2 binding with subsequent disruption in mismatch repair function, NPM-ALK as a HSP90 chaperone protein and vulnerable to HSP90 inhibitors, and the phosphorylation status of a number of other proteins. They close with a mention of NPM-ALK effects, both positive and negative, on miRNAs. In conclusion, we learn from them how much more is known about this fusion and its effects – a true example of sequential relevant discovery in molecular pathogenesis.

We close this issue with a comprehensive review of novel agents for indolent lymphomas, from M. Merli and colleagues at the University of Insubria, Varese, and University of Pavia, Italy. They begin with bendamustine, the ‘new/old’ alkylating agent with purine analogue properties, first studied and proven an effective (albeit short-lived) option after rituximab. When combined with rituximab, the same low toxicity profile was then coupled with longer duration remissions. Subsequent work has shown bendamustine+rituximab to better rituximab+CHOP with regards to PFS with no penalty in adverse events and moved this ‘old’ drug into a new spotlight. They then move to newer anti-CD20 antibodies, namely ofatumumab and obinutuzumab; both have single agent activity after prior therapies and continue in investigation in the front-line setting (ofatumumab) and the relapsed/refractory population (obinutuzumab). Additional novel antibodies include epratuzumab, directed against CD22 and showing good single agent activity and the potential to combine with rituximab; galiximab, a chimeric human-primate anti-CD80 with good initial relapsed/refractory data; the antibody-toxin conjugate inotuzumab ozigamicin (anti-CD22+calcheamicin), also showing promise in combination with rituximab; and blinatumomab, a bi-specific antibody able to enhance tumor lysis via engagement of cytotoxic T cells. The authors then delve into bortezomib and review its more limited single agent activity; the debate over schedule/intensity and toxicity (mainly peripheral neuropathy); combination results, limited but encouraging with rituximab, R-CHOP, and rituximab/bendamustine; and apparent selective activity in Waldenstroms macroglobulinemia. mTOR inhibitors, the PI3K inhibitor CAL-101, BTK inhibitors, BCL-2 family inhibitors as well as IMIDs are summarized as well, given their ongoing investigation in indolent lymphomas.

Enjoy!