Discussing the Diagnostic Process for Primary Myelofibrosis

Pankit Vachhani, MD (Moderator)

Assistant Professor

Department of Medicine

Hematologist/Oncologist

O’Neal Comprehensive Cancer Center

University of Alabama at Birmingham

Birmingham, AL

CASE SUMMARY

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 showed a JAK2 V617Fmutation. A bone marrow biopsy showed megakaryocyte proliferation and atypia with evidence of reticulin fibrosis. Blood smear revealed leukoerythroblastosis.

DISCUSSION QUESTIONS

• In your practice, do you rely on hematopathology to make a diagnosis, and/or do you use diagnostic criteria for myelofibrosis (MF)?
  • What challenges do you face in making a diagnosis?
• What other diseases need to be ruled out?
• What other mutational analysis would you perform and why?

ANDREW DALOVISIO, MD: [To make the diagnosis], I use diagnostic criteria, but I also have a discussion with our hematopathologist about what they’re seeing. It can be tricky to differentiate between secondary causes of fibrosis and other myeloproliferative neoplasms [MPNs], specifically those with overlapping features. Then we generally will do an extended next-generation sequencing [NGS] panel on all our patients for further risk stratification.

PANKIT VACHHANI, MD: Good to hear. Talking with a hematopathologist is very important. Sometimes when they look at a case, they don’t have the NGS results on hand, or they may not know the karyotype or that the patient has splenomegaly. Getting the picture together and talking with them can be very helpful.

What about cases where you don't get an aspirate, either because the bone marrow is fibrotic or because the biopsy couldn't be done as well as you thought it should have been? In that scenario, how do you get your NGS panel?

DALOVISIO: We’ll attempt it on the peripheral blood.

VACHHANI: I fully think that for MPNs, peripheral blood NGS is just as good as [NGS performed on] the bone marrow aspirate. Sometimes cytogenetics can become challenging if you don’t get aspirate. The karyotyping from peripheral blood can be difficult. The cells don’t grow. But yes, I fully support doing NGS from blood or from bone marrow. In fact, many times I send [for NGS from the peripheral] blood, and a bone marrow biopsy is scheduled a few days later. By that time, the NGS might already be back. I try to get a karyotype on every patient from bone marrow aspirate, but I agree that sometimes it can be challenging.

It's good to hear that you send an NGS panel, which is comprehensive, but is there anyone here who sends a very focused [assay]—JAK2, for example, or the combination of JAK2, CALR, and MPL—and not the entire panel?

JOSÉ L. MENDOZA, MD: I agree with what you’ve said. [If] we have a suspicious case for MF, with splenomegaly and constitutional symptoms—and if after examining in the peripheral blood, we have a leucoerythroblastic picture—we do a bone marrow biopsy. We try to do NGS on the liquid phase, and [we do] karyotyping as well, but I think the NGS has [particular] value because some specific abnormalities have been incorporated into certain staging systems. My last case of MF was one where, just based on the NGS finding, the patient qualified as a high-risk patient. If my suspicion is for any other possible MPN, I may start with a limited panel on the peripheral blood, as you mentioned.

If I think it’s MF, particularly if I am in doubt or if I am certain that the patient may be a candidate for stem cell transplant, then I would try to go for a bone marrow biopsy and try to get everything from there. If the aspirate doesn’t work, then we’ll move to blood. But with MF, [I try to use the] bone marrow first, [and I] try to get the liquid phase. If I am unable to do that, I get peripheral blood. If I have any other MPNs in mind, I would start with a JAK2 reflex panel [looking at] exon 12 and V617F mutations, CALR, and those things before we decide on the bone marrow biopsy. [I take] talking to the pathologist tremendously [seriously] when we’re thinking about MF. I have to wait. In cases where you think it’s going to be primary MF, it can end up being another tumor that’s infiltrating. I have also had [it happen] the other way around, when you see a lot of reticular fibrosis and [end up with] a diagnosis of primary MF.

VACHHANI: I agree that there are some mutations that can put patients at high risk. I get a comprehensive panel on everyone with suspected MF because it helps me [to assess their risk], to plan transplant and other future therapies, or to just give the patients some prognostic information, even if doesn't change the treatment.