Initiating Therapy for Myelofibrosis Based on Risk Assessment


During a Targeted Oncology case-based roundtable event, Rami Komrokji, MD, and participants discussed when to start treatment for patients with myelofibrosis.

Rami Komrokji, MD

Vice Chair, Department of Malignant Hematology

Head of the Leukemia and MDS Section

Moffitt Cancer Center

Tampa, FL

Rami Komrokji, MD

Vice Chair, Department of Malignant Hematology

Head of the Leukemia and MDS Section

Moffitt Cancer Center

Tampa, FL


A 68-year-old woman presented to her physician with symptoms of fatigue and abdominal pain lasting 4 months. She also reported increased bruising and unexplained weight loss. Her spleen was palpable 8 cm below the left costal margin. Genetic testing results showed a JAK2 V617F mutation. Bone marrow biopsy results showed megakaryocyte proliferation and atypia with evidence of reticulin fibrosis, and blood smear results revealed leukoerythroblastosis.

Laboratory results


Red blood cells



9.1 g/dL



Mean corpuscular volume

94 fL

White blood cells




Peripheral blood blasts



  • In your practice:​
    • What is the trigger to initiate therapy for a patient with myelofibrosis?​
    • What is the timing to start JAK (Janus kinase) inhibitor therapy, and how do you choose?​
    • How does the nature and burden of symptoms influence your decision to initiate JAK inhibitor therapy? ​
    • How important is it to initiate therapy early?​
    • When do you consider clinical trial enrollment? ​

RAMI KOMROKJI, MD: How do you start treatment in those patients? What triggers treatment? Is it the disease, patient symptoms, blood count? Do you believe initiation of therapy early is important? Those are all points that we do think of [for] every patient.

TIM NGUYEN, MD: Often the question I have for myself when I see a patient is when do you refer for [stem cell] transplant?

KOMROKJI: You are right on target, Dr Nguyen. The first thing is assessment. Is the patient at higher risk [so] that I should think of transplant? For that, we look at the disease risk. If they are higher risk or more, then it means that the patients’ survival by any of those models is going to be roughly around 3 years where you can justify the transplant rate of mortality. And then [there are] the host-related factors, their comorbidities, [and] their functional status. We are pretty aggressive. We transplant people up to age of 75 [or] 77, but the margin of benefit for patients based on the age varies. But that’s always the first question: Is this a patient that I’m going to consider for transplant or not, and that’s based on the disease risk more than anything else, which incorporates some of the symptoms as well.

RICARDO PARRONDO, MD: I initiate therapy when they have cytopenias, bothersome splenomegaly, [and] symptoms. I like the MIPSS70 [Mutation-Enhanced International Prognostic Score System] score because it incorporates the molecular aspect of it. So, if they’re high risk and at risk for AML [acute myeloid leukemia] transformation, you want to refer them to transplant before they transform to AML; then it’s even more difficult to manage. Also, if they’re between 70 and 75 years, the MIPSS70 will give you more information [to] tilt you towards whether you want to transplant them or not before they get too old and would have more comorbidities [and] more organ dysfunction. We should always consider clinical trial enrollment for these patients. Transplant is not a walk in the park for them; [they have] prolonged cytopenias [and] high mortality.

KOMROKJI: I agree....some of the molecular models predict more and they take out the age factor. If you use DIPSS [Dynamic International Prognostic Scoring System] or IPSS [International Prognostic Scoring System], I always say it’s counterintuitive to say [the patient] has only 1 risk factor, but because they are above 65, I am going to [suggest transplantation to] them now. I always depend on disease-related risk factors.

Sometimes you do treat those patients prior to transplant to improve their status, [in] patients that have [significant] splenomegaly. When I was a fellow in training, some of the transplanters used to talk about doing splenectomy before transplant to improve engraftment. Nowadays, we never talk about that, but some bridging with JAK2 inhibitors if patients were symptomatic is important.

To your point, if patients are not going to transplant, then it’s symptom-directed management. I try to think of the patients in 2 or 3 buckets; predominant symptoms, splenomegaly, and constitutional symptoms; that’s where the JAK2 inhibitors are indicated. Patients who are cytopenic—anemic, thrombocytopenic—there is no role of JAK2 inhibitors in that group. I saw a patient today coming in and they’re transfusion dependent, hemoglobin 6 g/dL but no splenomegaly, no constitutional symptoms and started on ruxolitinib [Jakafi]. What happens is that their hemoglobin drops down 2 g/dL more. But then the most challenging are the patients who do have splenomegaly, constitutional symptoms, and cytopenia, which sometimes don’t allow you, at least with the classic ruxolitinib, to get the meaningful dose to get them to response.

What would be your next step for this patient?

Initiate ruxolitinib ± refer for stem cell transplant
Initiate fedratinib ± refer for stem cell transplant
Initiate pacritinib ± refer for stem cell transplant
Refer for stem cell transplant
Clinical trial/Other

KOMROKJI: What would you do for this patient?

PARRONDO: I would say [to use ruxolitinib]. She has splenomegaly and constitutional symptoms. Her platelets are not too low, so she can tolerate ruxolitinib, and she has myelofibrosis.

KOMROKJI: Absolutely. I think 75% of the [participants] agreed with you, that they would start ruxolitinib and then refer to transplant. Fedratinib [Inrebic] is the drug that is very similar to ruxolitinib. Physicians have more experience with ruxolitinib. Pacritinib’s [Vonjo’s] niche is mainly for cytopenic patients with those symptoms. You could argue to refer them to transplant directly. But if the patient is symptomatic and you can get their performance better and shrink the spleen, there are some data that if patients responded to JAK2 and went to transplant, they do better.1 This patient does have higher-risk features, as Dr Parrondo mentioned. They are anemic, [have] circulating blasts, [and] that automatically [puts] them on a higher risk even without knowing the other molecular profile. This patient definitely needs a referral to transplant at least to consider.

UDAY DANDAMUDI, MD: Can I ask you a quick question on a similar case? A younger patient, 44 years old, CALR positive, notJAK2 [positive], but like the splenomegaly of 20 cm and hemoglobin of 10 g/dL to 11 g/dL; no other constitutional symptoms other than mild discomfort in the right upper quadrant. Do you think in that case, because it’s CALR, do you observe, or do you start the patient on treatment and send the patient to transplant?

KOMROKJI: That’s a good question. The age sometimes may make you think of taking the risk of transplant a bit earlier. But if the patient is CALR positive, splenomegaly per se is not a bad prognostic factor in any of the models. If the patient is lower risk, then I may wait on the transplant. Hemoglobin of 11 g/dL will not put them at risk. If they are not transfusion dependent nor [having] thrombocytopenia, I would look at the molecular profile. Do they have [mutations in] ASXL1, IDH, [etc]? If the patient [has risk of] intermediate or higher, at [the age of] 44, I would probably consider the transplant. If the main thing is just the splenomegaly, they don’t have other risk factors, and the splenomegaly is symptomatic, then I would go with JAK2 inhibitors in those patients. There are no guidelines on the size of the spleen to start the treatment. If they have mild splenomegaly, asymptomatic, sometimes I observe them as well. But if they have symptomatic splenomegaly, I will go for a JAK2 inhibitor.


Kröger N, Sbianchi G, Sirait T, et al. Impact of prior JAK-inhibitor therapy with ruxolitinib on outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis: a study of the CMWP of EBMT. Leukemia. 2021;35(12):3551-3560. doi:10.1038/s41375-021-01276-4

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