Degree of Anemia Influences Therapy for Myelofibrosis

Andrew Kuykendall, MD (Moderator)

Assistant Member, Department of Malignant Hematology

Moffitt Cancer Center

Tampa, FL

CASE SUMMARY

A 68-year-old woman presented to her physician with symptoms of mild fatigue. Spleen was palpable 6 to 7 cm below the left costal margin​. She had no known comorbidities​. Next-generation sequencing showed a JAK2 V617F mutation​. Bone marrow biopsy showed megakaryocyte proliferation and atypia with evidence of reticulin fibrosis​; blood smear revealed leukoerythroblastosis​. She received a diagnosis of primary myelofibrosis​ with Dynamic International Prognostic Scoring System intermediate-1​ risk. Laboratory values included hemoglobin of 9.7 g/dL, hematocrit 32.3%, and platelet count of 450,000/μL.

DISCUSSION QUESTION

• In your experience with myelofibrosis, which symptoms/presentations have the most negative impact on patients’ quality of life?​

Lazaros Lekakis, MD: [Symptoms with negative impact include] early satiety, fatigue, night sweats, bone pain, mood changes and minor attention problems, neurocognitive symptoms, but the main things are the [enlarged] spleen, anemia, and if they bleed from the thrombocytopenia. If they have a JAK2 [mutation], it can cause clots in the mesenteric vein or in the portal system.

Andrew Kuykendall, MD: Dr Lekakis covered a lot of ground there…. He also talked about neurocognitive or neuropsychiatric symptoms that are probably underappreciated in these patients, and some of the thrombotic issues as well. You can see a variety of symptoms that are impacting quality of life.

DISCUSSION QUESTIONS

• What is the trigger to initiate therapy?​
• How important is it to initiate therapy early?​

Jackson Gao, MD: I usually get started at diagnosis. Most of my patients are somewhat symptomatic with these very nonspecific symptoms, so I start ruxolitinib [Jakafi] right away.

Kuykendall: What have you noticed that improves the most in these patients with ruxolitinib?

Gao: In my experience, the splenomegaly is what improves the most.

Kuykendall: Dr Madadi, what's the trigger for you to start either ruxolitinib or another JAK inhibitor?

Anusha Madadi, MD: I use the NCCN criteria; splenomegaly, fatigue, pruritus, or worsening cytopenias would be indications for starting treatment. But now, with the overall survival [benefit shown for ruxolitinib,¹ because] the majority of the patients have some of the other symptoms, we start with ruxolitinib unless there is significant anemia or other cytopenias.

Kuykendall: That's fair. Does anyone have patients for whom you wait to start a JAK inhibitor until the symptoms are more prominent?

Ashok Kumar, MD: Especially with anemia and with fatigue, I feel starting early is better.

Lekakis: I have some patients for whom I didn't start therapy for many years, who sometimes go beyond the usual natural course of the disease. But eventually, all of them come for treatment. There are asymptomatic patients who have minimal symptoms, or they have a little bit of fatigue or a little bit of discomfort from the spleen. There are those patients who don't want to get treated, who hear the possible adverse events and say, “I will wait.” On the other hand, there have been some studies that show that there is probably some modification of the natural history of the disease; it’s modest, but there is something.^1,2

Kuykendall: It’s easy to think of a reflex to start all these patients on therapy, but then sometimes the patients read about the potential adverse events of these agents, and they come back [saying] "I don't know if I necessarily want to go on these things," and the data for disease modification are pretty weak. There are some studies that suggest there is some disease modification, but largely, these are agents that help with symptoms. It is more of a nuanced discussion.

DISCUSSION QUESTION

• When do you consider clinical trial enrollment?

Kuykendall: Are you thinking about clinical trials upfront, or is that something that is evaluated when sending a patient for a transplant evaluation, or after refractory disease?

Kwabena Osei-Boateng, MD: I work in the Levine Cancer Institute, so I tend to send most of my patients to see the leukemia and myeloproliferative [specialists], especially if they're intermediate or high risk. They already get assessed if there's a clinical trial, but they also have that conversation about transplant down the line before I even start anything.

Kuykendall: So you're sending these patients upfront at diagnosis.

Osei-Boateng: Most of them; there are some who don't want to [get a consultation].

Mukesh Kumar, MD: Most of my patients are older, and I'm 90 minutes from an academic center that does transplant. It becomes challenging [to enroll in] a clinical trial as well. We do start JAK inhibitors here.

Kuykendall: Most are saying to initiate ruxolitinib plus or minus referral for stem cell transplant. One responder said to just refer for stem cell transplant at this point in time. I would agree that’s probably my approach for this patient who has mild anemia, intact platelet counts, splenomegaly, constitutional symptoms, and seems like a good candidate for frontline ruxolitinib therapy. I would refer this patient for transplant to meet [the transplant physician], even though they have intermediate-1 risk. Transplant might not be something on the table right now, but sometimes that discussion is good to have earlier, rather than later.

Referring to the same patient, now we've changed the hemoglobin. Instead of 9.7 g/dL, our hemoglobin here is 7.8 g/dL. All other aspects of the case are the same. Would this alternate scenario change your approach for this patient?

Kuykendall: We've got a little bit of an even split saying yes vs no. How would this have changed your approach?

Lekakis: Momelotinib [Ojjaara] and pacritinib [Vonjo] give less anemia than ruxolitinib. Ruxolitinib, if you go with full dose, usually drops the hemoglobin by 1.5 g/dL. But with momelotinib or pacritinib, you may see the hemoglobin even go up a little.

Kuykendall: So with the anemia you don't want to drop her into the 6 g/dL range and have to start dealing with transfusions right off the bat. Let's see if we can get the same benefit, but also maintain that hemoglobin, maybe even improve it a little bit.

Madadi: I would say [something] similar, that momelotinib helps with the anemia. Especially with severe anemia, it would be more helpful.

Gao: I might just start out a lower dose of ruxolitinib and still try to treat the splenomegaly. I can see myself using momelotinib, but I would just probably just start at a lower dose of ruxolitinib.

Kuykendall: So give it a try and see what ruxolitinib does. We have a lot of experience with ruxolitinib. Let's see how the hemoglobin responds, and then, if we need to, maybe momelotinib is the backup plan. Does age or frailty factor into this at all? Is that a consideration when you're [treating] this patient? Does the patient being aged 68 factor into your decision-making?

Kumar: With frailty, if the symptoms are from the disease, I still try the medications. If symptoms are otherwise, if they have multiple comorbidities—I have a patient with Parkinson disease, and they have a lot of symptoms from the Parkinson disease and frailty. Then I'm thinking of what kind of medication I give him and what dose? Frailty does affect the treatment management.

_References:

_{1. Harrison CN, Vannucchi AM, Kiladjian JJ, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016;30(8):1701-1707. doi:10.1038/leu.2016.148}

_{2. Deininger M, Radich J, Burn TC, Huber R, Paranagama D, Verstovsek S. The effect of long-term ruxolitinib treatment on JAK2p.V617F allele burden in patients with myelofibrosis. Blood. 2015;126(13):1551-1554. doi:10.1182/blood-2015-03-635235}