Weighing the Triggers for Initiating JAK2 Inhibition Therapy in MF

CASE SUMMARY

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​, but she had no known comorbidities. Next-generation sequencing revealed a JAK2 V617F mutation​, and her karyotype was46XX.​ A bone marrow biopsy showed megakaryocyte proliferation and atypia with evidence of reticulin fibrosis​, and a blood smear was positive for leukoerythroblastosis​. Her laboratory values also led to a diagnosis of primary myelofibrosis (MF)​. Risk stratification based on the dynamic international prognostic scoring system gave her a score of intermediate-1​, and based on the mutation-enhanced international prognostic score system for transplantation-age she was also determined to be at intermediate risk​.

DISCUSSION QUESTIONS

• In your experience with MF, which symptoms/presentations have the most negative impact on patients’ quality of life?​
• ​In your practice:​
  • What is the trigger to initiate therapy for a patient with MF?​
  • What is the timing to start JAK inhibitor therapy, and how do you choose?​

RAAJIT K. RAMPAL, MD, PHD​: In patients with MF, what are the symptoms that have the most negative impact on a patient's quality of life. And then along those lines, what is your trigger to start therapy in patients with MF? [I will] say, this is something I always get a variety of opinions on. Is it important to initiate therapy early or not? And when do you consider clinical trials?

Raajit K. Rampal, MD, PhD​

Director, Center for Hematologic Malignancies

Director, Myeloproliferative Neoplasms Program

Memorial Sloan Kettering Cancer Center​

New York, NY

PRERNA MEWAWALLA, MD: I think the biggest [issue] that I see is the spleen, like splenomegaly. I think it can be very debilitating in these patients, and the second thing [to be aware of] is transfusion dependence.

RAMPAL: There are some patients who have had this disease for years, and the spleen grows gradually. Let's say you have [a patient] with a fairly massive spleen, maybe 15 to 20 cm below the left costal margin, but they've gotten used to it. They're not having an acute pain or anything like that, so does the spleen size itself ever trigger you to treat?

MEWAWALLA: Not if the patient is asymptomatic; generally [I will trigger treatment] if they're symptomatic.

ALEXANDER BARSOUK, MD: It's difficult to imagine somebody completely asymptomatic with their spleen 15 cm below costal margin. They would [most likely] have some symptoms. But other symptoms [to watch for] would be fatigue out of proportion to anemia or night sweats, [for example]. All this affects quality of life and that would be an indication, in my opinion, for treatment.

JOSE SILVA, MD: There is also the concern, if the spleen is very large, of [spleen] rupture. [For example], someone gets in a car accident and get squeezed by the seatbelt—if they have an enlarged spleen, that can be a concern [for rupture] as well.

RAMPAL: The consensus here is that if it's impacting quality of life, [that would trigger treatment initiation], and that makes a lot of sense. I have seen a fair number of these patients who, because the spleen has increased so gradually, they've become accustomed to it. I'm talking about people without the disease for 10 or more years. To some degree, [they might be] minimizing any symptoms or they're not aware that they're...being impacted by the spleen. These are the types of patients where, once you start therapy, then they realize they were compensating and getting used to it.

In those types of patients, I do press to initiate therapy because the problem is if one thinks about the data that we have with the JAK2 inhibitors, the likelihood of getting...a 35% spleen volume reduction—not that it's a magical number—decreases based on the dosing you can give patients.... Also, the proportional degree of reduction you're going to get on a practical level will diminish.... To me, I think once the spleen gets to a certain size, I try to encourage the patient to start therapy.