Defining and Treating Classic Cases of Myeloproliferative Neoplasms

CASE

• A 68-year-old woman presented to her physician with symptoms of mild fatigue.
• Her spleen was palpable 6-7 cm below the left costal margin​.
• Medical History: No known comorbidities
• Next-generation sequence testing: JAK2 V617F mutation​
• Karyotype: 46XX​
• Bone marrow biopsy: megakaryocyte proliferation and atypia with evidence of reticulin fibrosis​
• Blood smear: leukoerythroblastosis​
• Diagnosis: Primary myelofibrosis​
• Dynamic International Prognostic Scoring System: intermediate-1​
• Mutation-enhanced International Prognostic Score System 70: intermediate risk
• The patient was not interested in transplant​.
• A decision was made to initiate ruxolitinib (Jakafi).

Targeted Oncology: What makes myeloproliferative neoplasms (MPNs) unique among blood cancers?

PANKIT VACHHANI, MD: Every time I have a patient with chronic myeloid neoplasms, meaning a myeloid neoplasm that's not an acute leukemia, I like to think of it under the framework of World Health Organization 2022 classification schemes....¹ It's important because there are a few different subcategories of chronic myeloid neoplasms, one of which is MPNs. This [disease] used to be called myeloproliferative disorders, but around 2008 the name was formally changed to neoplasms...putting it into perspective, the fact that it is a blood cancer.¹

When looking at the category of MPNs, there are many of these...including the classic chronic myeloid leukemia, Philadelphia chromosome–positive MPN, and [more]. These also include polycythemia vera [PV], essential thrombocythemia [ET], myelofibrosis, pre-fibrotic and overt myelofibrosis, chronic neutrophilic leukemia, eosinophilic leukemia, and the MPN unclassifiable. Now, when we think of MPNs, the 3 classical Philadelphia chromosome–negative MPNs [specifically], include PV, ET, and myelofibrosis, which are the most common of the MPNs.

Pankit Vachhani, MD

Associate Professor

University of Alabama Birmingham Heerskink School of Medicine

Associate Scientist of Experimental Therapeutics

Hematology Oncology

Kirklin Clinic of UAB Hospital

Birmingham, Alabama

How do MPNs present in patients?

What connects all these MPNs is that they present somewhat similarly. They present with high white blood counts, or high blood counts in general, and they present [in patients] with symptoms, an enlarged spleen, for example. But if you've looked just at PV, ET, and myelofibrosis, what you will see is that there is a Janus Kinase [JAK]-STAT signaling pathway that is over activated.²

If you want to take a step back and think about it, we all know that there are cells and cells have receptors, receptors need lichens to be active, and one such receptor would be the erythropoietin [EPO] receptor. You need the EPO ligand to bind to the EPO receptor, and then the JAK would get activated and they would make the STATs activated and the activated STATs would go inside the nucleus and lead to transcription of different proteins.

What mutations are there in this disease?

The JAK-STAT pathway is involved in transmitting the signal from outside of the cell to inside of the nucleus, therefore making the changes.² What happens in PV, ET, and myelofibrosis is that this pathway is hyperactive; it doesn't even need a signal frequently to be over activated. In the case of PV, for example, most of the cases have a classic JAK2 V617F mutation, then a very small fraction [of the patients without this mutation have] either the JAK2 exon 12 mutation, or some very unusual [and rare] mutations….³ The same JAK2 V617F [mutation can] also be found in ET and myelofibrosis. In fact, that JAK2 mutation constitutes about 60% of myelofibrosis and ET cases.³

If you look at the [patients with] myelofibrosis, what happens to those remaining 40% of patients who don't have the JAK2 mutation? They have a CALR mutation or committal mutation, with CALR being the more common of those 2.³ About 10% of patients don't have a mutation in either of these 3 driver gene mutations and that's when we call it triple-negative myelofibrosis. Largely speaking, you are not going to find more than 1 of these mutations in the same case, so they’re more or less mutually exclusive. What's common, however, between all 3 [disease types] is that the all 3 leads to this JAK-STAT pathway being over activated.² So that's the commonality that connects MPNs.

What were the spleen reduction outcomes in the COMFORT-I study (NCT00952289)?

Data from COMFORT-1 showed that the 35% spleen volume reduction [SVR], which was a primary end point at 24 weeks, was met in about 42% of patients [given ruxolitinib] vs less than 1% of patients on placebo [P < .001].⁴ The SVR results were comparable with COMFORT-II [NCT00934544] with 28% of patients on jak[having a SVR compared with no one on the best available therapy].⁵

So, there was a massive difference [in these results] with ruxolitinib and the comparator.... If you look at the change in spleen response for individual patients...most patients who got ruxolitinib in COMFORT-I had a spleen volume that decreased. On the other hand, the patients who got placebo had an increase of spleen volume, and there were very similar data from the COMFORT-II study [showing SVR in individuals who got ruxolitinib].^4,5 Further, these results support ruxolitinib across the different subgroups, be that male vs female, primary or secondary myelofibrosis, or patients positive for the JAK2 mutation.

^References

^{1. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36(7):1703-1719. doi:10.1038/s41375-022-01613-1}

^{2. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379-90. doi:10.1056/NEJMoa1311347}

^{3. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391-2405. doi:10.1056/NEJMoa1312542}

^{4. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. doi:10.1056/NEJMoa1110557}

^{5. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-98. doi:10.1056/NEJMoa1110556}