Abstract. The association of essential thrombocythemia and multiple myelomais extremely rare, with only three patients previously treated with hydroxyureareported in the literature until now. In this paper, we report the case of a 66year old male who developed IgG-kappa M six years after the diagnosis ofessential thrombocythemia, for which he had received hydroyurea. The possibleetiological and pathogenic link between both these entities is here discussed.
1 Department of clinical hematologyarhat Hached, University Hospital,ousse, [email protected]>
2 Department of cytogenetics Farhatached, University Hospital, Sousse,unisia
3 Department of radiology Moknine,4 Department of anatomopathology
Résumé. L’association entre la thrombocytémie essentielle et le myélome mul-tiple est extrêmement rare, avec uniquement 3 cas traités par hydroxyuréerapportés par la littérature. Dans cet article, nous rapportons le cas d’un hommede 66 ans ayant développé un myélome multiple de type IgG kappa 6 ans aprèsle diagnostic d’une thrombocytémie pour laquelle il a été traité par hydroxy-urée. À travers une revue de la littérature, nous discuterons l’étiopathogénieexpliquant l’association de ces deux pathologies.
Mots clés : thrombocytémie essentielle, myélome multiple, hydroxyurée
arhat Hached, University Hospital,ousse, Tunisia
rticle received May 17, 2012,ccepted August 30, 2012
ssential thrombocythemia (ET) is a chronic myelopro-iferative neoplasm (CMN) that has been associated withransformation to acute leukemia, myelodysplastic syn-rome, chronic lymphoblastic leukemia and other CMNspecially primary myelofibrosis [1-4]. The association ofultiple myeloma (MM), a lymphoproliferative neoplasmith ET, a myeloproliferative neoplasm is extremely rare.e present here a patient who developed MM six years after
he diagnosis of ET, while he was receiving hydroxureaHu) treatment.
To cite this article: Ben Youssef Y, Gmidène A, Bouabid Z, Bouallegui S, Sriha B, Zaier M, SeAnn Biol Clin 2013; 71(4): 457-60 doi:10.1684/abc.2013.0856
ase report
66 year old Tunisian man with an history of hyper-ension treated by aspirin. He presented in October005 for thrombocytosis, he was asymptomatic and hishysical examination was unremarkable with no palpal
liver, spleen or lymph nodes. Complete blood cell count(CBC) showed marked thrombocytosis of 2770 G/L,normal hemoglobin (Hb=150 g/L), hematocrite concen-tration 44%, and hyperleukocytosis of 12.6 G/L. Resultsof serum analysis were within normal limits for fer-ritin, urea, creatinine, lactic deshydrogenase, C reactiveprotein (CRP) and protein electrophoresis. Abdominalultrasound examination revealed moderate splenomegaly15 cm sized. Bone marrow aspiration and biopsy were con-sistent with chronic CMPN-ET. Conventional cytogeneticsrevealed: 46,XY,?t(2;11)(p12;p13),?,del(6)(q21;q24) [12]
457nnana H, Khelif A. Multiple myeloma following essential thrombocythemia.
/46,XY [5]. JAK2/V617F mutation was positive. Therapywith Hu (1000-1500 mg/day) was initiated and continuedfor 6 years associated with aspirin, he was seen regularlywhen the platelet count was observed to be lower but notin the normal range. While on Hu therapy, he presented forasthenia and vomiting, serum creatinin level was elevated at260 �mol/L. He was admitted in nephrology department for
igure 2. Magnetic resonance imaging of that patient.
emodialysis. Erythrocyte sedimentation rate (ESH) was0 mm/h serum protein electrophoresis revealed a mono-lonal peak; the albumin level was 29 g/L and an elevatedotal protein level of 84 g/L was noted, that was associ-ted to a high globulin level at 16.4 g/L. A serum and urine
58
mmunofixation electrophoresis revealed IgG kappa clon-lity. Beta2 microglobuline was 2 mg/L (1.2-2.5 mg/L).he bone marrow aspiration and biopsy revealed atypicallasma cell infiltration of 20% (figure 1). MRI imaginghowed vertebral lytic lesions (figure 2), so the diagnosisas a Durie Salmon stage IIIB and international staging
ystem (ISS) stage I disease. A combination chemotherapy
with melphalan-thalidomide and prednisone was started.After one course of chemotherapy, we noted normalizationof creatinine levels at 60 �mol/L.
Ann Biol Clin, vol. 71, n◦ 4, juillet-août 2013
Discussion
Myeloproliferative neoplasms (MPN) inclusing poly-cythemia vera (PV), ET and primary myelofibrosis (PMF),are rare disorders with an annual incidence rate of 2.1 per100.000 person years. The course of MPN complicatedmainly by vascular events and transformation to myelofi-
Journal Identification = ABC Article Identification = 0856 Date: July 24, 2013 Time: 10:47 am
A
Multiple myeloma following essential thrombocytemia
Table 1. Essential thrombocythemia (ET) treated by hydroxyurea (Hu) followed by MM: reported cases in the literature.
Case References Age/sex Initial Time interval Therapy for Evolution
bwRwplofMEtc[TiEfaliacoiMwonmIEmpaeflmdTvSaK
neoplasm: a study of 1,915 patients. Haematologica 2011 ; 93 : 454-8.
diagnosis (years)1 Majhail et al. [6] 85/M ET 52 Majhail et al. [6] 54/M ET 33 Eskazan et al. [1] 48/F ET 34 Our case 66/M ET 6
rosis and leukemia, secondary malignancies may occurith a low incidence.umi et al. [5] had noted that, among 1915 patientsith MPN, 1.1% of patients developed lymphoid neo-lasm over their life time chronic lymphocytic leukemia, Tymphoblastic lymphoma, chronic lymphoproliferative dis-rder, diffuse large B-cell lymphoma, mulyiple myeloma,ollicular lymphoma. . . The most frequently associated
PN with MM is polycythemia vera; the association ofT with MM is unfrequent and the reason of this associa-
ion remains unclear [1]. An explanation for this associationould be the treatment with busulfon and Hu for MPN1, 6].o our knowledge, our patient is the fourth case documented
n the literature of patients who had received Hu alone forT and then developed MM (table 1). Two cases of MM
ollowing ET [7, 8] and one case of plasma cell leukemiafter ET [9] receiving Busulfon and Hu were reported in theiterature. Cobo et al. [10] reported one case of MM follow-ng ET for which the patient had received alpha interferonnd radioactive phospohore (32P). Another hypothesis thatould explain the association of MM and ET is the existencef pluripotent stem cell with the capacity to differenciatento both lymphoid and myeloid cells [1, 6, 11].
PNs are characterized by a state of chronic inflammationhich is considered of major importance in the devel-pment of several cancers including certain hematologiceoplasms. They are also characterized by elevated inflam-atory markers such as CRP, IL-6, fibrinogen, IL-7, IL-8,
L-6 is a potent human myeloma cell growth factor [12].levated creatinine level may be du either MM and toyeloproliferative glomerulopathy. It was proposed that
latelet-derived growth factor TGF-� might probably haven important role when considering that both cytokines arelevated in patients with ET and plateled derived growthactors is a very potent stimulus of mesangial cell pro-iferation and indices extracellular matrix production by
esangial cells. Chronic inflammation may facilitate renal
nn Biol Clin, vol. 71, n◦ 4, juillet-août 2013
ysfunction in MPN patients [12].he JAK2-V617F mutation induces constitutive acti-ation of downstream signaling pathways, includingTAT3/STAT5 induction of cell cell proliferation (STAT5)nd neutrophil activation (STAT3). By triggering The NF-B and JAK pathways, STAT3 also activates the production
initial disorderHu Platelet normal when MM was diagnosedHu Platelet normal when MM was diagnosedHu Platelet elevated when MM was diagnosedHu Platelet elevated when MM was diagnosed
of enzymes (metalloproteinases), cytokines (IL-6, IL-10,IL-7 and IL-23), and growth factors. Accordingly, STAT3may be a key regulator of cancer associated inflammationin MPNs eliciting and substaining angiogenesis (highlyexpressed in MM) in bone marrow [12].
Conclusion
In the perspective that chronic inflammation and improvedtumor immune surveillance may be important factor withthe pathogenesis and pregression of MPNs, it seems rationalthat JAK1-2 inhibitor with association of TNF� may bea rational approach with the potential of inhibiting clonalexpansion and there by interruption the inflammation drivenincrease of several cytokines (TNF�, IL-6) [12].
Conflicts of interest: to declare.
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