The Year's Best in Myeloproliferative Neoplasms

Last year brought multiple advances in the field of myeloproliferative neoplasms (MPNs), including novel insights in triple-negative MPNs, the molecular underpinnings of calreticulin (CALR) -mutated MPNs, new treatments for systemic mastocytosis (SM), and long-term data for patients with chronic myeloid leukemia (CML).

“Triple-negative” is no longer a term restricted to breast cancer; in the context of MPNs, it refers to cases negative for the driver mutations JAK2, MPL, or CALR. Triple negativity represents approximately 10 percent of individuals with primary myelofibrosis (PMF) and essential thrombocythemia (ET). Two separate studies, led by Dr. Jelena D. Milosevic Feenstra and by Dr. Xénia Cabagnols, identified alternative driver mutations in patients with triple-negative MPNs.^1,2  In the multi-institutional European study led by Dr. Feenstra,¹  10 percent (seven of 69 patients) of those with triple-negative ET and PMF had non–exon 10 MPL mutations, and 9 percent (five of 57 patients) had JAK2 mutations other than V617F and exon 12.¹  Dr. Cabagnols and colleagues from France and Belgium similarly found alternative MPL mutations in cases of triple-negative ET by using whole-exome sequencing and next-generation sequencing.²  These data show that by using traditional laboratory methods, we are overlooking variant MPL and JAK2 mutations. Therefore, a robust, targeted panel of mutations in MPNs using next-generation sequencing–based approaches is recommended. Even so, at least 80 percent of triple-negative MPNs are still without a known driver mutation.

Since the 2013 discovery of CALR mutations, further studies have provided exciting insights into the pathogenesis of CALR-mutated MPNs. A murine model of the CALR mutation–induced MPL-independent thrombocytosis, with the type 1 mutation (52–base pair deletion) leading to a phenotype of myleofibrosis, splenomegaly, and osteosclerosis.³  The putative disease mechanism underlying the pathogenesis of CALR-mutated MPNs was also uncovered in 2016. The mutated CALR protein was found to activate MPL (the thrombopoietin receptor), resulting in constitutive activation of JAK-STAT signaling.^4,5  The binding of mutated CALR to MPL is independent of thrombopoietin, and the positive charge of the C-terminus of CALR was found to be critical for its transforming capacity. These findings have unmasked a new disease paradigm in which a mutated chaperone protein can induce cytokine activation and overt MPN disease. Another interesting discovery was the association of the CALR mutation with myeloperoxidase (MPO) deficiency. MPO deficiency was observed in 7 percent of PMF cases (six of 81 patients), and five of these 6 patients were found to have a homozygous CALR mutation.⁶  Patients with homozygous CALR mutations had reduced MPO protein, but normal MPO messenger RNA levels, consistent with a posttranscriptional defect in MPO production. The investigators demonstrated in vitro that in the absence of CALR, immature MPO protein precursors undergo degradation in the proteasome.

2016 was also a standout year for the orphan disease SM. Proof-of-principle has now been demonstrated that clinical benefit can result from inhibiting KIT D816V — the mutated receptor tyrosine kinase that drives disease pathogenesis in 90 percent of SM patients. Dr. Jason Gotlib and colleagues reported on a global, single-arm, phase II clinical trial of the multikinase/KIT inhibitor in patients with advanced SM.⁷  Midostaurin elicited partial or complete reversion of SM-related organ damage in 60 percent of patients, with most subjects showing a reduction in bone marrow mast cell burden and/or serum tryptase levels by more than 50 percent.⁷  Additionally, the majority of patients exhibited reduction in splenomegaly and improvement of symptoms and quality life. A trial is currently underway for patients with midostaurin in indolent SM led by Dr. Hanneke Kluin-Nelemans in the Netherlands. These data set the stage for evaluating a new generation of selective KIT D816 inhibitors, including BLU-285, whose preliminary phase I data were presented by Dr. Daniel Deangelo in an oral session at the 2016 ASH Annual Meeting.⁸  Significant progress has also been made in the molecular landscape of SM. Dr. Mohamad Jawhar and colleagues found that mutations in SRSF2, ASXL1, or RUNX1 (S/A/R) were associated with an adverse prognosis in SM⁹ ; both the S/A/R mutation profile and a reduction of the KIT D816V allele burden by less than 25 percent were associated with inferior outcomes with midostaurin treatment.¹⁰ 

Tyrosine kinase inhibitor (TKI) regimens and risk stratification have brought about advances in CML treatment in 2016. Long-term follow-up data from the phase III ENESTnd trial showed that nilotinib resulted in earlier and higher response rates and lower risk of progression to accelerated disease over five years when compared with imatinib. Cardiovascular events were more common with nilotinib but were rarely associated with death.¹¹ To reduce adverse effects of nilotinib, a phase II study was designed to alternate nilotinib with imatinib during first-line treatment. Data indicate that cardiovascular events are reduced when compared with other nilotinib studies and that this regimen would decrease costs for the patient.¹²  A follow-up study from the EUTOS population-based registry summarized first-line TKI treatments and outcome data from 2,904 patients with CML, and will serve as a benchmark for future therapeutic investigations.¹³  Dr. Preetesh Jain and colleagues followed BCR-ABL1 p210 transcript types in chronic-phase CML patients treated with first- and second-generation TKIs. The study found that patients with e14a2 (b3a2) transcripts, when compared with e13a2 (b2a2) transcripts, achieved earlier and deeper treatment responses, which also predicted longer event-free and transformation-free survival.¹⁴  New prognostic data were collected in a study that stratified chromosomal evolution in CML following treatment with TKIs. Aberrations with favorable prognosis included trisomy 8, -Y, and an extra copy of Philadelphia chromosome, whereas poor prognostic aberrations included i(17)(q10), –7/del7q, and 3q26.2 rearrangements.¹⁵ 

Finally, the 2016 ASH Annual Meeting provided further data on cessation of TKI therapy in chronic-phase CML patients treated with imatinib, nilotinib, or dasatinib. In patients achieving a minimum of one year of a deep molecular response (e.g., BCR-ABL1 <0.01% on the international scale), molecular relapse-free survival (MRFS) was 62 percent at six months, 56 percent at 12 months, and 52 percent at 24 months, respectively. Longer duration of imatinib therapy (optimal, ≥ 5.8 years) prior to TKI-stop was associated with a higher probability of MRFS. In the British De-Escalation and Stopping Therapy with Imatinib, Nilotinib, or sprYcel (DESTINY) study, patients in at least stable MR3 (e.g., <0.1% on the international scale) decreased their TKI to half the standard dose for 12 months, followed by complete cessation. Molecular recurrence was lower in patients with stable MR4 (compared to lower than MR4), and neither progression to advanced phase nor loss of cytogenetic response was observed. The study found that reducing the TKI to half the standard dose was safe, and was associated with improvement in TKI-related side effects, indicating that some patients with stable long-term responses may be getting over-treated.