Impressive thrombocytosis evolving in a patient with a BCR-ABL positive CML in major molecular ...

189 Pages·2015·0.29 MB·English

Pastoreetal.ExperimentalHematology&Oncology2013,2:24
http://www.ehoonline.org/content/2/1/24 Experimental
Hematology & Oncology
CASE REPORT Open Access
Impressive thrombocytosis evolving in a patient
with a BCR-ABL positive CML in major molecular
response during dasatinib treatment unmasks an
additional JAK2V617F
Friederike Pastore1,2*, Stephanie Schneider1, Oliver Christ1, Wolfgang Hiddemann1,2 and Karsten Spiekermann1,2
Abstract
We present a case ofa 42-year old femalewith therare diagnosis of a myeloproliferative syndrome harboring both
a BCR-ABL transclocation and a JAK2V617F mutation.
Initially diagnosed with a CML, thepatientunderwent treatment with imatinib followed by dasatinib.Despite a
major molecular response, the patient developed a thrombocytosis. Molecular analysesrevealed a heterozygous
JAK2V617F mutation,which was detected retrospectivelyin thebone marrow at thetime of CML diagnosis.
Thiscase underlines the complexity of MPS pathogenesis.For the clinician, a JAK2 mutational screening should be
performed in CML patients without hematological response in the absence of BCR-ABL.
Keywords: BCR-ABL, JAK2V617F, CML, MPS
Case presentation syndrome therapy was changed to imatinib (400 mg/
In March 2005 a 42-year old woman presented with a day)inApril2005.
leukocytosis of 350 G/l, a thrombocytosis of 498 G/l Under the treatment with imatinib the patient achieved a
and an elevated lactate dehydrogenase (LDH) level of completehematologicalremissionwithintwomonths.Since
2207 U/l. The differential blood count showed 47% cytogenetic and molecular remission was not obtained even
neutrophils, 14% myelocytes, 11% promyelocytes, 10% after one year of therapy with imatinib, a mutation analysis
myeloblasts, 5% metamyelocytes, 5% eosinophils, 5% of BCR-ABL was performed in October 2006, which re-
basophilsand3%lymphocytes. vealednoevidenceforpointmutationswithintheBCR-ABL
The diagnosis of a typical chronic myeloid leukemia kinase domain. After an initial decrease, theBCR-ABL/ABL
(CML) was established after detection of an aberrant ratio continuously increased from 3.4 to 33.3 in February
karyotype 46,XX,t(9;22)(q34;q11) in all 25 metaphases 2009.Thepatientwasrecommendedtoincreasethedoseof
and the presence of the BCR-ABL-rearrangement (98%) imatinib,whichshedeclined.
in the bone marrow aspirate by FISH. The quantitative In June 2009, the patient developed a hematological
BCR-ABL/ABL ratio determined by RT-PCR was 53.0. relapse of the CML with leukocytosis (24 G/l), throm-
The spleen was enlarged with 22.5 cm. The patient was bocytosis (853 G/l) and elevated LDH level (290 U/l).
classified aslowriskaccording to Sokal [1] and Hasford Interphase FISH detected 59% BCR-ABL positive cells
[2]riskscoresforsurvival. and the BCR-ABL/ABL ratio was markedly elevated
After an initial treatment with hydroxyurea resulting (48.13). Therapy was changed to a second line regimen
in a rapid cytoreduction with an initial tumor lysis withdasatinib(Figure1).
Within three months of therapy with dasatinib, a
hematological response with normalization of the white
*Correspondence:[email protected]
1LaboratoryforLeukemiaDiagnostics,DepartmentofInternalMedicineIII, blood count (WBC) and platelet count, as well as a
UniversityHospitalMunich–CampusGrosshadern,Munich,Germany complete cytogenetic (no BCR-ABL positive nuclei in
2ClinicalCooperativeGroup,PathogenesisofAcuteLeukemia,Helmholtz
Center,Munich,Germany
©2013Pastoreetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and
reproductioninanymedium,providedtheoriginalworkisproperlycited.
Pastoreetal.ExperimentalHematology&Oncology2013,2:24 Page2of5
http://www.ehoonline.org/content/2/1/24
1000 platelets 1000
WBC
800 800
P
al
)l/G 600 600 elet
( CB uoc t
W n
400 400 G( t
)l/
200 200
0 0
2005 2006 2007 2008 2009 2010 2011
100 100
%)
H ( 10 10
S
FI ol
s in 1 1 ar g
ell oit
e c cb
sitiv 0.1 0.1 ba-r
po a/l
abl lb
cr- 0.01 bcr-abl (FISH) 0.01
b bcr-abl/abl ratio
0.001 0.001
2005 2006 2007 2008 2009 2010 2011
100
JAK2V617F/JAK2wt ratio
wt
2
K
JA 10
F/
7
1
6
V
2
K
A
J
o 1
ati
g r
o
l
0.1
2005 2006 2007 2008 2009 2010 2011
Time (years)
HU Imatinib Dasatinib
Figure1Summaryofbloodcounts,molecularanalysesandcytoreductivetherapyinapatientwithaCMLwithJAK2V617Fclonal
evolutionundertreatmentwithimatinibanddasatinib.
Pastoreetal.ExperimentalHematology&Oncology2013,2:24 Page3of5
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FISH) and a partial molecular remission (BCR-ABL/ developed a BCR-ABL positive CML and other patients
ABLratiodroppedto0.6)wasrecorded. that suffered a CML who developed features of a PV
A major molecular response, with a normal karyotype [15,16],anET[17]oranOMF[18,19].
andaBCR-ABL/ABLratio <0.1(0.04)inthe quantitative TheJAK2V617Fmutationwasshowntoprecedetheac-
RT-PCRwasdiagnosedinOctober2010. quisition of BCR-ABL [10,14], co-occur with [16,19,20]
Until March 2013 repeated molecular and cytogenetic andalsosucceed[15,21]theBCR-ABLfusiontranscript.
analyses showed a constant complete cytogenetic and In the published literature data are still controversial
majormolecular remission. concerningtheaspectifPhiladelphiachromosomenegative
DespitetheabsenceofthePhiladelphiachromosome,the MPS and CML develop as separate diseases originating
patient developed and retained a marked thrombocytosis from different stem cells, or if these entities evolve from a
andelevatedLDHlevelsagainsinceFebruary2010. mutual cell of origin by the acquisition of JAK2V617Fand
Therefore, a JAK2-V617F mutation analysis was theBCR-ABLfusiongeneatdifferenttimepoints.
performed in October 2010, which demonstrated a Some authors favor the hypothesis, that a single sub-
heterozygousV617F[3]. cloneofprogenitorcellscarryingaJAK2V617Fsuccessively
The amount of the mutated JAK2-allel was quantified acquires the BCR-ABL translocation [10]. Those cells ac-
with the MutaQuant™ kit from Ipsogene. Retrospective quireaproliferativeadvantage,butdisappearwhenexposed
analyses of gDNA from peripheral blood or bone mar- to imatinib. In contrast, the clone harboring JAK2V617F
row samples from the first diagnosis until June 2010 re- onlywillnotbesensitivetoimatinib.
vealed that the JAK2 mutant allel had already been Other models postulate that a JAK2V617F and the
present in the bone marrow at first diagnosis at a very BCR-ABL fusion derive independently parallel from sus-
lowlevel(ratioJAK2V617F/JAK2wt :0.122). ceptible polyclonal stem cells [15,22-24] or might be
The amount of JAK2 mutant allel was constant in 2006 preceeded by another independent genetic hit (founder
andshowedarapidincreasein2007(from1.091inJanuary mutation)whichpredisposestotheiracquisition[18].
to 6.754 in May) under treatment with imatinib. In June In our patient, at initial diagnosis a JAK2V617F was de-
2006, when the CML relapse was diagnosed and therapy tectable at a very low level whereas the BCR-ABL clone
was changed to dasatinib, the JAK2V617F/JAK2wt ratio wasalready100%oftheCMLclone.Consideringthemere
was 9.9 and further increased since then to 30.3 in May frequenciesthissuggeststhatthetwomutationsmighthave
2011. Thus, both, BCR-ABL and JAK2V617F coexisted arisenindependentlyindifferentbonemarrowcells.
simultaneously. Whereas leucocytosis was due to genetic Nevertheless, applying the hypothesis of Bocchia et al.
abnormalities,persistantthrombocytosiswasmainlycaused [10]thisdoesnotexcludethepossibilitythattheBCR-ABL
bytheJAK2V617F. positive clone might have represented a sub-clone of
JAK2V617F mutated cells which had gained a growth
Conclusion and discussion advantage.
Wepresent a patient witha BCR-ABLpositiveCMLwho Under therapy with imatinib the JAK2 mutant level in-
achieved a major molecular response after second line creased suggesting a growth advantage of JAK2V617F posi-
treatment with dasatinib. Occurrence of an impressive tive/BCR-ABL negative cells in relation to JAK2V617F
thrombocytosisandelevatedLDHlevelsintheabsenceof positive/BCR-ABL positive cells which might have been at
BCR-ABLledtothediagnosisofanadditionalJAK2V617- leasttosomedegreeantagonizedbyimatinib.Theseobserva-
positive clone. Retrospectively, the JAK2V617F mutant tionsareinlinewiththefactthatCMLtherapywithimatinib
was already detectable at a very low level simultaneously was shown to reveal Philadelphia chromosome negative
toBCR-ABL atfirst diagnosis ofCML. This isa rare case clonaldisordersinmorethan10%ofCMLpatients[25].
unmasking a JAK2V617F-positive clone in a patient with Finally, therapy with dasatinib might have eliminated the
aBCR-ABLpositiveCML. JAK2F617F-positive/BCR-ABLpositiveclone.Thesuppres-
JAK2isatyrosinekinasethatplaysanimportantrolein sionoftheBCR-ABLclonemighthavefacilitatedgrowthof
the signalling pathways of myeloid hematopoietic cells. A the JAK2V617F-positive cells without the BCR-ABL fusion
singleacquiredactivatingpointmutationinJAK2(V617F) that were unaffected by dasatinib. This theory is supported
occursinthemajorityofBCR-ABLnegativeMPSsuchas by continuously rising levels of the JAK2V617F/JAK2wt
ET, PVand OMF [4-7], but is only rarely found in BCR- ratio and progressive thrombocytosis and leukocytosis in
ABLpositiveCML[8,9]. our patient. This is in line with the so called “gene dosis
The hypothesis, that BCR-ABL and JAK2V617Fare mu- hypothesis” meaning that JAK2V617F expression level cor-
tuallyexclusive[8]hasbeendisprovedinthelastfewyears. relate with the number of involved cell lines and thus the
There have been reports about patients with a previous type of disease (low level ->ET; high level ->PV) [26,27].
history of a JAK2V617F positive polycythemia vera (PV) The increase of platelets to>1000 G/l was followed by an
[10-12], ET [13] or osteomyelofibrosis (OMF) [14] that increaseofleukocytes.
Pastoreetal.ExperimentalHematology&Oncology2013,2:24 Page4of5
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doi:10.1186/2162-3619-2-24
Citethisarticleas:Pastoreetal.:Impressivethrombocytosisevolvingin
apatientwithaBCR-ABLpositiveCMLinmajormolecularresponse
duringdasatinibtreatmentunmasksanadditionalJAK2V617F.
ExperimentalHematology&Oncology20132:24.
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