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Biology and Targeting of Eosinophilic MPNs
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Hi, I'm Jason Gotlib. I'm at the Stanford Cancer Institute in Stanford, California, and I'm excited to be here at SOHO 2016. I'm going to be talking about the biology and targeting of eosinophilic MPNs.

This transcript is software driven, please understand there may be errors.  Should any inaccuracies or omissions be found, please notify for correction.

Hi, I'm Jason Gotlib. I'm at the Stanford Cancer Institute in Stanford, California, and I'm excited to be here at SOHO 2016. I'm going to be talking about the biology and targeting of eosinophilic MPNs.

When the hematologist addresses the patient with hypereosinophilia, it's my practice to go to a diagnostic algorithm and I first ruled out reactive causes of eosinophilia. If there are none found, then the first part of the workup is to look for the FIP1L1 platelet-derived growth factor receptor alpha fusion by FISH and RT-PCR and look for other breakpoints that are associated with these eosinophilic MPNs, such as for platelet-derived growth factor receptor beta, fibroblast growth receptor-1, or fusions involving JAK2. If none of those are found then, basically, there's a dealer's choice of other possible categories of eosinophilias.

That includes WHO-defined myeloid neoplasms with eosinophilia, chronic eosinophilic leukemia not otherwise specified. There is a variant called lymphocyte variant hypereosinophilia, which is meted by t-cell clones elaborating eosinophilic cytokines producing yeast level counts, which is not a developed MPN but it's another category to consider.

If none of these entities are found, we’re left with idiopathic hypereosinophilic syndrome, if organ damage is present, or idiopathic hypereosinophilia if no organ damage is found. I think one of the most important things that the practitioner should know about is knowing your breakpoints on standard karyotyping.

In this slide we have the breakpoints for PDGFR alpha, PDGFR beta, ABL, FGFR1, JAK2, and FLT3. Why is this important? Well, this provides opportunities for targeted therapy and also there are differences in the prognosis of patients. Very important in addressing the work-up of patients, and also potential treatment options.

Let's first just briefly talk about the entity FIP1L1 platelet-derived growth factor receptor alpha myeloid neoplasms. This is due to an interstitial deletion in chromosome 4 through 12, which deletes the CHIC2 gene, and thus when the diagnostic test for this entity is FISH for the CHIC2 deletion. With this deletion, we bring together the genes FIP1L1 and platelet-derived growth factor receptor alpha. This is a fusion oncogene, which drives eosinophilia.

We now have more than a decade worth of experience about this entity. It is known that less than 10% of patients who present with idiopathic hypereosinophilia in developed countries have this myeloid neoplasm associated with eosinophilia. Most patients are male. This is not visible by standard sight genetics, and thus the need for FISH or RT-PCR to diagnose it. These patients are often referred to as having a myeloproliferative variant of hypereosinophilia. These patients have bone marrow fibrosis, atypical mast cells in the bone marrow, often times have splenomegaly, and they rarely present with AML associated with eosinophilia.

It's very noteworthy that these individuals are exquisitely sensitive to treatment with imatinib. A dosage lower than that, which is used in CML: for example, 100 milligrams per day. Patients rapidly achieve hematologic and complete molecular remissions. These patients have durable response to imatinib and very good survival. There are rare cases of acquired resistance to imatinib, probably less than 20 cases in the literature, and almost exclusively due to the T674I or D842 mutation within platelet-derived growth factor receptor alpha. These are patients that are often put on alternative tyrosine kinase inhibitors such as erlotinib. Frankly, the responses are variable, not durable, and these are patients that ultimately need to go transplant.

Well, what about platelet-derived growth factor receptor beta rearranged myeloid neoplasms? There are some 25 fusion partners to PDGFR beta. These are patients that usually present it with an MDS or MPN overlap, or CMML and really present in myeloid blast phase or have an associated b- or t-cell lymphoblastic leukemia. The diagnosis can be made with standard karyotyping by finding a 5q31 to q33 breakpoint. PCR and FISH are used to diagnose the fusion definitively, also find the fusion partner. In these patients, treatment with imatinib 400 milligrams per day is recommended, and these patients also have a very good long-term prognosis.

There is another entity, which is the FGFR1 rearranged neoplasms. These are very aggressive disorders. They present with an MPN usually associated with eosinophilia, or AML, but also can present with an associated b- or t-cell lymphoma, and sometimes with mast cells in the bone marrow as well. The diagnosis is made by finding an 8p11-12 breakpoint. This is disease that's been historically referred to as stem cell leukemia/lymphoma or 8p-11 myeloproliferative syndrome.

Because these patients have very aggressive disease, it is often recommended they undergo intensive AML or ALL induction chemotherapy followed by transplant. It's noteworthy that these are patients that also may be amenable to targeted therapy with FGFR1 inhibitors. The problem currently is that we don't have very selective FGFR1 inhibitors, so ponatinib has been used and FGFR1 inhibitors are currently in development. These are patients again that have a very poor prognosis. If they have an MPN, it usually terminates in AML in a very short period of time, usually about 1 to 2 years. Transplant as an option is key.

I mentioned that there are patients who have MPNs with eosinophilia that actually have rearrangement of JAK2. This is in contradistinction to the JAK2 V617F mutation. However, knowing that there's a JAK2 rearrangement in these patients does provide an opportunity for targeted therapy with JAK2 inhibitors such as ruxolitinib.

In this slide we see two examples of patients. One with a PCM1-JAK2 fusion, another patient with a BCR-JAK2 fusion that had been treated with ruxolitinib. These patients achieved a hematologic remission and complete cytogenetic remissions. Those responses were actually fairly short-lived and ultimately these are patients that needed to undergo a transplant in order to get prolonged disease-free survival.

There is another entity that should be noted and that is chronic eosinophilic leukemia not otherwise specified. These are patients that have either increased blasts in the peripheral blood or bone marrow, or have a nonspecific cytogenetic abnormality that's not one of the rearrangements that I previously alluded to. These patients typically have a poor prognosis, although frankly there are sparse data regarding the natural history of these individuals. Treatment has usually surrounded the use of hydroxyurea, [PEG]-interferon-alpha, and, in some cases, imatinib, transplant, and often times we want to recommend a clinical trial because the other options are not very palatable.

None of these diagnosis are evident—that is, one doesn't define the rearrangement of PGFR alpha or beta, FGFR1, or JAK2, or one can identify a WHO-defined myeloid neoplasm associated with eosinophilia, such as MDS or mastocytosis or another MPN or MDS/MPN overlap. Or, we don't find a chronic eosinophilic leukemia that is increased blasts or cytogenetic abnormalities. We're left with a diagnosis of idiopathic hypereosinophilic syndrome.

These are patients that have durable eosinophilia and not a chromal cytogenetic or molecular abnormality. We have found recently that this appears to be a shrinking pool of patients, because when next-generation sequencing or standard karyotyping is applied, more and more of these patients are found to have molecular or cytogenetic abnormalities and are therefore redefined as some form of chronic eosinophilic leukemia.

These are patients that have traditionally been treated with corticosteroids as first-line therapy, or hydroxyurea. There are data, usually based on case series, of using interferon or [PEG]-interferon-alpha, and in such instances there are patients that are able to achieve cytogenetic remissions, hematologic remissions, and actually reversion—in some cases, organ damage. Alternatively, imatinib has been used on an off-label basis. Compassionate use antibody mepolizumab, or transplant, and, of course, a clinical trial option.

This is data from the MD Anderson group, specifically Wang and colleagues. Actually it’s a study of this issue of interrogating patients with HES to see whether they have mutations in one or more myeloid genes that have been found in other neoplasms. In fact, some 28% of the patients with HES were found to have one or more myeloid mutations, which then reclassifies these patients as a chronic eosinophilic leukemia.

In a study with a look at the long-term survival of the HES patients, those that had myeloid mutations actually did worse compared to those that didn't have any mutations. In turn, those that had mutations had a long-term prognosis that was similar to those of patients with chronic eosinophilic leukemia, which generally again is relatively poor.

Just to summarize the issue of eosinophilic MPNs, in this age we believe that standard karyotyping and targeting molecular profiling are critical to identifying the subtype of eosinophilic neoplasm. Eosinophilia is a very common but not invariable feature of rearrangements involving PDGFR alpha or beta, FGFR1, or JAK2.

The prognosis of these disorders really depends on the specific rearrangement and required consideration of TKIs (that, is tyrosine kinase inhibitors), which are very useful for PDGFR alpha- and beta-rearranged disease, but not particularly useful for patients with the FGFR1 or JAK2 rearrangements. These are patients where TKIs can be used, I think, as a bridge to ultimately what is needed and that is transplant.
Finally, next-generation myeloid panels, or exome sequencing, may be very useful for implicating genes that reclassify patients with HES to more or a chronic eosinophilic leukemia. Finding such mutations may in some cases provide opportunities for targeted therapy and give a better idea of prognosis.

Thank you very much for listening to this presentation regarding eosinophilic MPNs, biology, and targeting therapy.