#27 myeloproliferative update

8/9/2019 #27 Myeloproliferative Update

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The myeloproliferative

neoplasms: an update

Gene R. Shaw, M.D.

August, 2008


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The large majority of myeloproliferativeneoplasms can confidently be placed in one of

the following categories.

Chronic myelogenous leukemia (CML)

Polycythemia vera (PV)

Essential thrombocythemia (ET)

Primaryidiopathic myelofibrosis (PMF)

Refractory anemia with ringed sideroblasts andthrombocytosis (RARS-T)**RARS-T currently in the MDS/MPN category


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Chronic myelogenous leukemia

(CML) Conventional cytogenetics (usually BM) at

diagnosis and then q 1-2 years

Q RT-PCR (usually peripheral blood) afterabout 6 months and then ~q 6 months;currently send to BC of WI

Dont needbaseline (but not a bad idea)

Expressed in log reduction units

Major molecular response: > 3 log reduction

Complete molecular response: not detectable


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BCR/ABL Tyrosine Kinase

Inhibitor Analysis

> 100 different mutations causing resistance

More common ones stratified for degree ofresistance: T315I most resistant

Various methods

Different types of sequencing, double gradient

denat. electroph., etc

Best if not too sensitive; small clones may not

be clinically significant


6/31

BCR/ABL Tyrosine Kinase

Inhibitor Analysis

When to order

2.6 fold increase = 0.4 log fold increase

Oregon/German study (Blood, 2009. 114:2598)

Mayo Laboratories

Mfld client fee $3-400 range


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Imatinib (Gleevec)

Drug Levels Available through GIST/CML Alliance

No charge currently

Collected in special kits

Trough levels < 1,100 ng/ml: trend towardlower rate of clinical response and fastertime to progression

Occasional patient; e.g. obese and questionif standard dose is sufficient


8/31

Q: Do you need to do bcr-abl on

all MPNs to rule out CML? NO (despite what some articles say).

Conventional cytogenetics detect > 95% ofCML

cases

CBC parameters and BM morphology can usually

distinguish between CML and other MPNs

JAK-2 V617F mutation almostmutually exclusive

ofPh/bcr-abl

Only 4 of 2317 MPDs in German study


9/31

Q: Is there any role for leukocyte

alkaline phosphatase?

NO.

Way too nonspecific.

Weve discontinued it at Marshfield


10/31

Polycythemia Vera (PV)

Peripheral blood

Increased Hb, but not always if iron deficient

Increased RBC, low MCV

Numbers can look like thalassemia

RBC > 6 million/uL in males

RBC > 5 million/uL in females


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PV

Erythropoietin

Low (in perhaps half of cases): essentially seals

the diagnosis

Normal or slightly high: not very helpful

Moderately to very high: rules out except

when in post-polycythemic myelofibrosis stageand anemic


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JAK2 V617F mutation

Gain of function mutation; epo

independent erythroid colony formation

9p24 exon 14

Sensitive; positive in 90-95% ofPV cases Thus a negative result calls the diagnosis ofPV into

question No correlation with conventional cytogenetic

findings


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JAK2 V617F mutation

But nonspecific within the non-CML

MPNs; also positive in about half ofET,

PMF, and RARS-T cases

Otherwise rarely positive: perhaps 2-5% of

CMML cases and < 2% of various MDS

cases


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JAK2 V617F

Thus, a positive JAK2 V617F mutation

essentially establishes a diagnosis of a non-

CML MPN, but doesnt specify the subtype.

PV tends to have a greatermutational

burden (preferred term; instead of trying to

establish homo- or heterozygosity), butcurrently no standard method to determine

this


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JAK2 exon 12 mutations May be idiopathic erythrocytosis

Normal white count and platelet count with only

erythroid hyperplasia in BM. Scott, et al.NEJM

.2/1/07. Usually low epo

Some cases (perhaps 10-20%; wide variation in reportsto date) haveJAK2 exon 12 mutations

Not widely available; a variety of mutations---thus,

probably requires sequencing. Avaibable at M.D.Anderson in Houston, TX

May be a panmyelosis and fulfill standard PVdiagnostic criteria JAK2 negative PV.


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Promising JAK2 inhibitors

Lestaurtinib (Univ ofPA)

WP 1066 (M.D. Anderson)

JG 101348 (Harvard, UC San Diego)

TG101209

CEP-701 (M.D. Anderson)

INCBO18424 (COMFORT Imyelofibrosis

study advertised in Blood)


17/31

Q: Whats the role of red cell

mass measurements In my opinion completely unnecessary (despite

what Jerry Spivak at Johns Hopkins continues to

say) Can be normal in patients with iron deficiency

Not normalized for obesity (red cell mass correlates

better with lean body mass)

Not widely available; requires radioactive reagents I dont trust em. Anecdotally have seen several

patients with misleading results


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Occult PV in Budd-Chiari

syndrome

Roughly 50% of patients with Budd-Chiari

syndrome or splanchnic vein thrombosis

will be positive forJAK2 V617F

This subset may have a worse prognosis,

but based on limited number of cases


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Primary Myelofibrosis (PMF) Peripheral blood

Counts all over the map

Often increased poik (tear drops and/or nucleated reds)and a few blasts

Bone marrow

Often dry tap

Increased reticulin fibrosis

Increased giant megakaryocytes

Exclude post-polycythemic phase ofPV


20/31

Q: Is the cellular phase ofPMF a

real entity?

Doubt it. It cant be reliably recognized,

even by experienced hematopathologists

Wilkins, et al. Blood. 1/1/08.


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MPLW515L/K mutations MPL is the thrombopoietin (TPO) receptor

These mutations result in hypersenstivity to TPO

Occur in ~ 5-10% ofPMF and 1-5% ofET cases

Independent (with or without) ofJAK2 mutations

Clinically pretty similar to those without this mutation;

PMF pts with them are more often anemic, but thats

pretty obvious already

M.D. Anderson offers test, but currently no

pressing clinical need


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Essential thrombocythemia (ET) Isolated increase in platelets (now 450,000) and

megakaryocytes

No or minimal dysplasia in other cell lines Pretty minimal myelofibrosis

1-5% have MPL mutations

Rule out

Post splenectomy: Howell-Jolly bodies and targets cells Inflamatory related: clinical presentation (e.g recent surgery), high

CRP

Iron deficiency (do not diagnose; recall that PV often irondeficient)


23/31

Q: Are cases ofET orPMF with the

JAK2 V617F mutation different; arethey really occult PV?

Good question.

They seem to have some features ofPV; e.g. aslightly higher Hb and RBC

ET pts with JAK2 V617F have more arterialthrombotic events (several studies from different

countries) and possibly increased risk of fetal loss

JAK2negative PMF pts may have shortersurvival


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JAK2- positive cases: Early pre-

polycythemic phase ofPV vs ET?

ET patients that go on to develop PV

In ET like to see Hb < 15 g/dl males


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RARS-T

Mixed MPD/MDS

About 50-70% have JAK-2 V617F mutation

Need to distinguish from refractory

cytopenia with multilineage dysplasia

Usually normal cytogenetics and good

prognosis

Shaw. BrJHaematol. 131:180-184. 2007


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The cutting edge:

TET2 Mutations

Ten-eleven translocation involves TET1

Subsequently family of TET genes

discovered

Recent interest in TET2 gene at 4q24

Putative tumor suppressor gene

Usually PCR followed by sequencing


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TET2 Mutations Seen in approximately 10-25% of myeloid

malignancies in general

MPNs: prognostic impact currently unknown Mayo study (2010): 199 MPN pts

25 (12.5%) had a mutation

Averaged 10 years older

But no notable differences in conventional cytogeneticabnormalities


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TET2 Mutations MDSs

French study (2009): 22 of96 pts mutated

Betteroverall survival when TET2 mutated

Multivariate analysis adjusting for age, IPSS, etc

Chronic myelomonocytic leukemia (CMML)

Same French group (2009): 44 or 88 pts mutated Trend forworse overall survival


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Q: What if the patient has

hypereosinophilia?

Thats a whole nother talk

#27 myeloproliferative update

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