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A subset of patients with myeloproliferative neoplasms (MPNs) -- clonal disorders of hematopoietic stem cells that include polycythemia vera and essential thrombocythemia, as well as primary myelofibrosis -- will transition to post-MPN, or secondary, acute myeloid leukemia (AML).

"Some people call it AML -- I like to make the distinction and call it accelerated or a blast-phase MPN, because it does behave a little bit differently than just good old-fashioned de novo AML that arises on its own," said Aaron Gerds, MD, of the Cleveland Clinic. "It is more aggressive, and more difficult to treat, and with shorter remissions with traditional chemotherapy."

Post-MPN AML is as the presence of 20% or more myeloblasts in the peripheral blood or bone marrow of a patient with an antecedent myeloproliferative disorder, and is most likely to occur in patients with myelofibrosis, with estimates showing an of transformation within the first 10 years after diagnosis.

Of note, post-MPN AML has an extremely poor prognosis.

"The median overall survival for post-MPN AML is approximately 6 months -- less than a year from diagnosis," said Naveen Pemmaraju, MD, of the University of Texas MD Anderson Cancer Center in Houston. One showed a median survival of just 2.6 months from the time of leukemic transformation.

Risk of Progression

"This form of progression can be predicted somewhat by the presence of adverse mutations," Gerds explained, adding that when a patient is diagnosed with an MPN, "we are always looking for driver mutations" -- in this case JAK2, CALR, and MPL mutations -- "but it is other mutations that predict a higher risk of progression. We see mutations in genes like ASXL1 or TP53 that predict a higher risk of progression to accelerated or blast-phase disease."

Pemmaraju noted that very few patients with chronic myelofibrosis have TP53 mutations. "When we sequence patients when they are going through the accelerated blast phase to leukemic transformation, a great many of them will be enriched for TP53 mutations. Those are patients who did not have it before."

"So the conclusion is that at the time of transformation, patients are dynamically acquiring de novo new mutations that are being picked up and leading to the accelerated-phase or blast-phase leukemic transformation," he said.

Gerds explained that chromosome testing can be done, "which looks at large groupings of genes and chromosome abnormalities that can predict for that as well."

"There are some studies that suggest that a higher white blood cell count can predict for progression, and age is associated with a higher risk of progression, but those are very imprecise predictors," he added. "They are probably predicting for the presence of other factors, such as mutations that predict for progression, so they are like a predictor of a predictor, so they're not as accurate."

Monitoring for Progression

Pemmaraju pointed out that the majority of patients with low- to medium-risk chronic myelofibrosis can survive for decades and have a very low risk of leukemic transformation. However, patients who have medium- to high-risk disease "are the patients you monitor closely," he noted.

"So built into every myelofibrosis or MPN patient visit, we are looking at complete blood cell counts," Pemmaraju said. "We ask everyone to get a differential count, which tells you the type of white blood cell blast ... that many times can be the first harbinger. If you see the complete blood cell counts showing abnormalities (increasing blasts in the peripheral blood), that may trigger ... bone marrow biopsy, which is gold standard."

Other clues that the disease is progressing include patient symptoms, including B symptoms -- drenching night sweats, fatigue that is progressive, and unintentional weight loss -- and anemia or thrombocytopenia.

"So there are different buckets suggesting a patient is transforming," Pemmaraju said. "No matter what those buckets are, they must be confirmed with a bone marrow biopsy."

The speed at which transformation occurs "is something we are actively studying," he noted. "We used to think transformation could take years or decades, but there is a subset of patients who are so high risk -- they may have multiple molecular mutations, for example -- some of them can actually transform months after presentation."

"It's quite variable for some patients," Gerds said. "For some patients it may take years, and slowly the numbers start to increase and you kind of get a sense that this might happen in 6 or 12 months. Then, sometimes, it seems like it is almost overnight. You check the blood counts and everything looks fine, and the next time you check, the blasts are high. Both patterns are present, which shows there is a role for routine monitoring in order to catch these things as they happen."

Pemmaraju pointed out that "it is shocking when it happens in the clinic and you have someone who progresses that quickly. It either means the disease was brewing under the radar, or it was such a high-propensity disease that it just happened quickly."

A 'Stunning' Difference in Outcomes

In terms of outcomes, the difference between patients who have de novo AML or post-MPN AML is "stunning," Pemmaraju observed.

According , treatment-specified 3-year and 5-year survival rates were 32% and 10%, respectively, for patients receiving allogeneic stem cell transplantation, and 19% and 13%, respectively, for chemotherapy-induced patients in complete remission or complete remission with incomplete count recovery and who were not transplanted, while the 3-year survival rate was only 1% in the absence of both allogeneic stem cell transplant and chemotherapy induction.

As far as delaying or even preventing a transition into AML, "we haven't got there yet," Pemmaraju said. "The goal remains to improve or decrease spleen volume -- which is often a surrogate for other disease markers, potentially even overall survival with these JAK inhibitors -- and improve symptoms."

He noted that while several JAK inhibitors -- including ruxolitinib (Jakafi), fedratinib (Inrebic), pacritinib (Vonjo), and momelotinib (Ojjaara) -- have been approved for the treatment of myelofibrosis, there are no approved agents specifically for post-MPN AML.

"The search is on for preclinical targets for these patients," Pemmaraju said. "Overall survival is so poor for many of our patients, we badly need new therapies. The only curative strategy ... particularly in younger, fit patients, is to try to get them to allogeneic stem cell transplant -- but unfortunately many patients can't get there because the disease is not in remission, it is too resistant to chemotherapy, or they have other comorbidities."

"I advise my own mentees, and other investigators getting into the field, to really focus on preclinical translational efforts in post-MPN AML," he added.

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