Precision immunotherapy, mutational landscape, and emerging tools to optimize clinical outcomes in patients with classical myeloproliferative neoplasms

Abstract

Following the 47th American Society of Hematology Meeting in 2005, the late John Goldman and Tariq Mughal commenced a conference, the 1st Post-ASH Workshop, which brought together clinicians and scientists, to accelerate the adoption of new therapies for patients with myeloproliferative neoplasms (MPNs). The concept began with recognition of the CML success story following imatinib therapy, the discovery of JAK2 , and the demonstration that BCR-ABL1-negative MPNs are driven by abnormal JAK2 activation. This review is based on the presentations and deliberations at the XIIth Post-ASH Workshop on BCR-ABL1 positive and negative MPNs that took place on December 12 to 13, 2017, in Atlanta, Georgia, immediately following the 59th American Society of Hematology Meeting. We have selected some of the translational research and clinical topics, rather than an account of the proceedings. We discuss the role of immunotherapy in MPNs and the impact of the mutational landscape on TKI treatment in CML. We also consider how we might reduce TKI cardiovascular side effects, the potential role of nutrition as adjunctive nonpharmacologic intervention to reduce chronic inflammation in MPNs, and novel investigational therapies for MPNs.

Chronic Myeloproliferative Neoplasms: Some Remaining Challenges

“…These include hedgehog, aurora kinase, SMAC, HDAC, and MDM2 inhibitors, in addition to the JAK2-allosteric inhibitors, such as LS104 and ON044580, which have a greater specificity for JAK2 V617F and are inhibitory in a non-ATP-competitive manner, and were recently reviewed. 24…”

“…[21][22][23] Other areas of clinical importance include prediction of resistance to TKIs by assessing BCR-ABL1 mutant subclone expansion, particularly in those who display 2 or more mutations in the BCR-ABL1 kinase domain. 24 The best treatment approaches for pediatric patients remain unclear. Recent work has confirmed the use of dasatinib as an effective treatment, with a safety profile similar to that seen in adults, though, interestingly, no examples of pleural or pericardial effusions or pulmonary arterial hypertension were noted.…”

“…These include hedgehog, aurora kinase, SMAC, HDAC, and MDM2 inhibitors, in addition to the JAK2-allosteric inhibitors, such as LS104 and ON044580, which have a greater specificity for JAK2 V617F and are inhibitory in a non-ATP-competitive manner, and were recently reviewed. 24 The success of targeted therapy for patients with CML in CP has been contingent upon BCR-ABL1 being the founder lesion in every cell, and minimal genetic diversity. Resistance can be an issue, but many patients can achieve durable second and subsequent remissions, following a switch to an alternative TKI or an allogeneic stem cell transplant.…”