{"id":1066,"date":"2017-01-31T13:58:21","date_gmt":"2017-01-31T12:58:21","guid":{"rendered":"http:\/\/www.newslab.sk\/2017\/01\/31\/dlhodoba-molekulova-remisia-ako-predpoklad-uspesneho-tehotenstva-u-pacientok-s-chronickou-myelocytovou-leukemiou\/"},"modified":"2017-10-03T10:45:59","modified_gmt":"2017-10-03T08:45:59","slug":"long-lasting-molecular-remission-as-a-precondition-for-successful-pregnancy-in-female-patients-with-chronic-myeloid-leukemia","status":"publish","type":"post","link":"https:\/\/www.newslab.sk\/en\/long-lasting-molecular-remission-as-a-precondition-for-successful-pregnancy-in-female-patients-with-chronic-myeloid-leukemia\/","title":{"rendered":"Long-lasting molecular remission as a precondition for successful pregnancy in female patients with chronic myeloid leukemia"},"content":{"rendered":"
*All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf <\/span><\/strong>\r\nattachment at the end of the paper.<\/span><\/strong><\/pre>\n
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\u00da<\/strong>vod<\/strong><\/p>\n
Chronick\u00e1 myelocytov\u00e1 leuk\u00e9mia (CML) je klon\u00e1lne myeloproliferat\u00edvne ochorenie vych\u00e1dzaj\u00face z transformovanej kme\u0148ovej pluripotentnej hematopoetickej bunky, pri ktorom dominuje prolifer\u00e1cia granulopo\u00e9zy. Typickou pre t\u00fato diagn\u00f3zu \u00a0je recipro\u010dn\u00e1 \u00a0translok\u00e1cia dlh\u00fdch ramien chromoz\u00f3mov 9 a 22, t(9;22)(q34;q11), pri\u010dom s danou cytogenetickou odch\u00fdlkou, tzv. chromoz\u00f3mom Philadelphia \u00a0(Ph), je spojen\u00e1 \u00a0pr\u00edtomnos\u0165\u00a0f\u00fazneho g\u00e9nu B<\/em>C<\/em>R<\/em>–<\/em>A<\/em>BL <\/em>(1). Tento abnorm\u00e1lny \u00a0f\u00faznyg\u00e9n produkuje onkoprote\u00edn BCR-ABL, ktor\u00fd predstavuje\u00a0 kon\u0161titut\u00edvne akt\u00edvnu tyroz\u00ednkin\u00e1zu. Hlavn\u00fa skupinu liekov predstavuj\u00fa inhib\u00edtory tyroz\u00ednovej kin\u00e1zy (TKI), ktor\u00fdch zavedenie do praxe znamenalo revol\u00faciu v lie\u010dbe CML.<\/p>\n
Imatinib bol prv\u00fdm z inhib\u00edtorov tyroz\u00ednkin\u00e1z, ktor\u00fd bol pou\u017eit\u00fd na lie\u010dbu pacientov s CML u\u017e v roku 1998. Je pova\u017eovan\u00fd za liek prvej l\u00ednie u chor\u00fdch s novodiagnostikovanou CML v chronickej f\u00e1ze ochorenia (2, 3), predov\u0161etk\u00fdm u pacientov s n\u00edzkym rizikom pod\u013ea Sokala. Pre pacientov s rezistenciou alebo intoleranciou na imatinib boli vyvinut\u00e9 tzv. inhib\u00edtory tyroz\u00ednkin\u00e1z (dasatinib a nilotinib) druhej gener\u00e1cie. Ke\u010f\u017ee boli schopn\u00e9 navodi\u0165 r\u00fdchlej\u0161ie a dlhodobej\u0161ie lie\u010debn\u00e9 odpovede v porovnan\u00ed s imatinibom, v s\u00fa\u010dasnosti s\u00fa dostupn\u00e9 \u00a0aj ako lieky 1. l\u00ednie pre pacientov s CML. Dasatinib je dostupn\u00fd ako lie\u010dba 1. l\u00ednie vo svete, na Slovensku len ako lie\u010dba 2. l\u00ednie. Nilotinib je mo\u017en\u00e9 pou\u017ei\u0165 ako lie\u010dbu 1. l\u00ednie aj na Slovensku u pacientov so stredn\u00fdm a vysok\u00fdm rizikom pod\u013ea Sokala a u pacientov v akcelerovanej \u00a0f\u00e1ze (4, 5). Pod\u013ea ELN odpor\u00fa\u010dan\u00ed je mo\u017en\u00e9 u novodiagnostikovan\u00fdch pacientov v chronickej f\u00e1ze za\u010da\u0165 lie\u010dbu imatinibom 400 mg alebo nilotinibom 600 mg, alebo dasatinibom 100 mg, bez oh\u013eadu na rizikov\u00e9 sk\u00f3re pod\u013ea Sokala.<\/p>\n
V mana\u017emente pacientov s CML sa pou\u017eit\u00edm TKI dosahuje optim\u00e1lna lie\u010debn\u00e1 odpove\u010f (6). V\u00e4\u010d\u0161ina pacientov je schopn\u00e1 pod ich vplyvom udr\u017ea\u0165 ochorenie CML pod kontrolou, a t\u00fdm zlep\u0161i\u0165 kvalitu \u017eivota. Najnov\u0161ie klinick\u00e9 \u0161t\u00fadie zalo\u017een\u00e9 na dlhoro\u010dn\u00fdch sk\u00fa\u0161aniach zameriavaj\u00fa svoje ciele na mo\u017enos\u0165 ukon\u010denia lie\u010dby s TKI u t\u00fdch pacientov s CML, u ktor\u00fdch sa dosahuje dlhodob\u00e1 a z\u00e1rove\u0148 hlbok\u00e1 molekulov\u00e1 odpove\u010f. Tento z\u00e1mer je nesporne ve\u013emi d\u00f4le\u017eit\u00fd v pr\u00edpade CML pacientok, ktor\u00e9 pl\u00e1nuj\u00fa tehotenstvo. Napriek tomu, \u017ee CML je diagnostikovan\u00e1 u pacientov vo vy\u0161\u0161om veku (55 \u2013 60 rokov), pod\u013ea registra GIMEMA je a\u017e 50 % pacientov s touto diagn\u00f3zou v reproduk\u010dnom veku. Hoci v s\u00fa\u010dasnosti pou\u017e\u00edvan\u00e1 cielen\u00e1 terapia umo\u017e\u0148uje pacientom vies\u0165 plnohodnotn\u00fd \u017eivot, pod\u013ea dostupn\u00fdch inform\u00e1ci\u00ed sa odpor\u00fa\u010da po\u010das u\u017e\u00edvania TKI vhodn\u00e1 met\u00f3da\u00a0 antikoncepcie. Teratog\u00e9nne \u00fa\u010dinky TKI v skorom \u0161t\u00e1diu tehotenstva sa podpisuj\u00fa na mno\u017estve fet\u00e1lnych abnormal\u00edt. Bol op\u00edsan\u00fd ich vplyv na spont\u00e1nne potraty a na skelet\u00e1lne malform\u00e1cie (pred\u010dasn\u00e9 uzavretie lebe\u010dn\u00fdch \u00a0\u0161trb\u00edn, kraniosynost\u00f3za, anom\u00e1lie ramien, skoli\u00f3za), ren\u00e1lne (zdvojen\u00e1 obli\u010dka, agen\u00e9za obli\u010dky), respira\u010dn\u00e9 (hypopl\u00e1zia p\u013e\u00fac) a gastrointestin\u00e1lne (omfalok\u00e9la) abnormality (6, 7).<\/p>\n
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Z<\/strong>as<\/strong>t<\/strong>a<\/strong>venie lie\u010dby s TKI u pacientov v chronickej f\u00e1ze CML<\/strong><\/p>\n
Predpokladom \u00a0zastavenia lie\u010dby s TKI je dosiahnutie optim\u00e1lnej lie\u010debnej odpovede u pacientov v chronickej f\u00e1ze CML, ktor\u00e1 je definovan\u00e1 pod\u013ea odpor\u00fa\u010dan\u00ed \u00a0European LeukemiaNet \u00a0(3, 8). Hodnotenie odpovede \u00a0na lie\u010dbu u pacientov s CML lie\u010den\u00fdch \u00a0TKI je monitorovan\u00e9 \u00a0v presne stanoven\u00fdch \u010dasov\u00fdch intervaloch (3, 6 a 12 mesiacov), pri\u010dom sa posudzuje odpove\u010f na \u00farovni cytogenetiky, fluorescen\u010dnej i<\/em>n situ <\/em>hybridiz\u00e1cie (FISH) a kvantitat\u00edvnej polymer\u00e1zovej re\u0165azovej reakcie v re\u00e1lnom \u010dase (qRT-PCR). Molekulov\u00e1 remisia sa vy\u0161etruje v 3 \u2013 6-mesa\u010dn\u00fdch intervaloch pri optim\u00e1lnej odpovedi. Za optim\u00e1lnu odpove\u010f sa posudzuje hladina transkriptov B<\/em>CR<\/em>–<\/em>A<\/em>B<\/em>L \u00a0<\/em>\u2264 10 % a\/alebo pr\u00edtomnos\u0165 Ph+ \u2264 35 % po 3 mesiacoch od za\u010datia lie\u010dby; \u2264 1 % a\/ alebo Ph+ = 0 po 6 mesiacoch; a \u2264 0,1 % po 12 mesiacoch lie\u010dby. V\u00e4\u010d\u0161ina pacientov v chronickej f\u00e1ze CML je schopn\u00e1 dosiahnu\u0165 dlhodob\u00fa cytogenetick\u00fa a molekulov\u00fa odpove\u010f, pri\u010dom hlavn\u00fdm cie\u013eom lie\u010dby je dospie\u0165 k ve\u013ekej molekulovej odpovedi \u00a0(MMR), ktorej dosiahnutie do 1 roka od za\u010datia lie\u010dby sa pova\u017euje za v\u00fdznamn\u00fd prediktor hlbokej molekulovej odpovede.<\/p>\n
Stabiln\u00e1 MMR sa sp\u00e1ja s dlhodobou absenciou progresie ochorenia do akcelerovanej a blastovej f\u00e1zy (9, 10) a vedie k mo\u017enosti zastavenia lie\u010dby s TKI u \u010dasti pacientov. Franc\u00fazska klinick\u00e1 \u0161t\u00fadia STIM (Stop Imatinib) uk\u00e1zala, \u017ee imatinib m\u00f4\u017ee by\u0165 vyraden\u00fd z lie\u010debn\u00e9ho procesu u t\u00fdch pacientov, ktor\u00ed dosahuj\u00fa stabiln\u00fa kompletn\u00fa molekulov\u00fa remisiu (CMR)\u00a0(nedetekovanie transkriptu B<\/em>C<\/em>R<\/em>–<\/em>A<\/em>BL \u00a0<\/em>met\u00f3dou qRT-PCR) po obdobie minim\u00e1lne dvoch rokov. Vo vzorke 100 pacientov 61 % z nich zrelabovalo na molekulovej \u00farovni v priebehu 6 \u2013 7 mesiacov. Hoci u v\u00e4\u010d\u0161iny pacientov v relapse bola pozorovan\u00e1 odpove\u010f na opakovan\u00fa lie\u010dbu, nie v\u0161etci z nich boli schopn\u00ed sp\u00e4tne dosiahnu\u0165 CMR. Na\u010falej ost\u00e1va nejasn\u00fd dopad prechodnej straty optim\u00e1lnej odpovede, a preto sa v s\u00fa\u010dasnosti, s v\u00fdnimkou klinick\u00fdch \u0161t\u00fadi\u00ed, neodpor\u00fa\u010da preru\u0161enie lie\u010dby TKI (11).<\/p>\n
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M<\/strong>an<\/strong>a<\/strong>\u017e<\/strong>m<\/strong>e<\/strong>n<\/strong>t tehotenstva u pacientok s CML<\/strong><\/p>\n
Odpor\u00fa\u010dania na lie\u010dbu pacientok s CML po\u010das tehotenstva s\u00fa v\u00fdzvou pre hematol\u00f3gov \u00a0a gynekol\u00f3gov, ke\u010f\u017ee vzh\u013eadom\u00a0 na vz\u00e1cnos\u0165 tohto ochorenia v gravidite nie je dostatok inform\u00e1ci\u00ed ani klinick\u00fdch \u0161t\u00fadi\u00ed. Doposia\u013e sa preuk\u00e1zalo, \u017ee medi\u00e1n pre\u017e\u00edvania pacientov s nelie\u010denou CML je pribli\u017ene 30 mesiacov, t. j. n\u00e1stup progresie ochorenia \u00a0nie je pr\u00edli\u0161 r\u00fdchly (12). Na z\u00e1klade tejto skuto\u010dnosti je m\u00e1lo pravdepodobn\u00e9, \u017ee sa rezistencia alebo progresia CML objav\u00ed v relat\u00edvne kr\u00e1tkom \u010dase po\u010das tehotenstva. Napriek tomu rezidu\u00e1lne CML bunky m\u00f4\u017eu sp\u00f4sobi\u0165 progresiu ochorenia, a vtedy musia by\u0165 pacientky lie\u010den\u00e9 aj v gravidite. Dostupnou lie\u010debnou alternat\u00edvou v gravidite je interfer\u00f3n-\u03b1, ktor\u00fd s\u00edce prech\u00e1dza placent\u00e1rnou bari\u00e9rou a m\u00f4\u017ee \u00a0zv\u00fd\u0161i\u0165 riziko reproduk\u010dn\u00fdch \u00a0str\u00e1t, no napriek tomu m\u00e1 len mierne nepriazniv\u00e9 \u00fa\u010dinky na v\u00fdvoj plodu (13).<\/p>\n
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S<\/strong>\u00fab<\/strong>o<\/strong>r pacientov a met\u00f3dy<\/strong><\/p>\n
Ke\u010f\u017ee na\u0161\u00edm cie\u013eom bolo pouk\u00e1za\u0165 na nutnos\u0165 dosiahnutia dlhotrvaj\u00facej ve\u013ekej molekulovej remisie u pacientok s CML pri pl\u00e1novan\u00ed gravidity ako predpokladu \u00faspe\u0161n\u00e9ho zvl\u00e1dnutia tehotenstva, prin\u00e1\u0161ame 2 kazuistiky pacientok v reproduk\u010dnom \u00a0veku. MMR po obdobie \u00a0minim\u00e1lne dvoch rokov sa pova\u017euje za indik\u00e1tor \u00faspe\u0161nej \u00a0obnovy \u00a0lie\u010dby TKI po p\u00f4rode, ktor\u00fd sa odzrkad\u013euje v op\u00e4tovnom\u00a0 dosiahnut\u00ed MMR v kr\u00e1tkom \u010dasovom horizonte.<\/p>\n
Vzorky perif\u00e9rnej \u00a0krvi (PK) a kostnej drene (KD) na molekulov\u00e9 vy\u0161etrenie boli odoberan\u00e9 \u00a0do sk\u00famaviek s EDTA a z\u00e1rove\u0148 do TEMPUS sk\u00famaviek, ktor\u00e9 obsahuj\u00fa stabiliza\u010dn\u00fd roztok zamedzuj\u00faci \u00a0degrad\u00e1cii RNA. Do transportu a po\u010das neho boli uchov\u00e1van\u00e9 pri teplote 4 \u2013 10 \u02daC.<\/p>\n
Na stanovenie transkriptov f\u00faznych g\u00e9nov B<\/em>CR<\/em>–<\/em>A<\/em>B<\/em>L \u00a0<\/em>sa vyu\u017e\u00edva met\u00f3da molekulovej \u00a0anal\u00fdzy, kvantitat\u00edvna polymer\u00e1zov\u00e1 \u00a0re\u0165azov\u00e1 reakcia v re\u00e1lnom \u010dase (qRT-PCR). DNA (cDNA) f\u00faznych g\u00e9nov je pou\u017eit\u00edm hydrolyza\u010dn\u00fdch TaqMan sond \u0161pecificky amplifikovan\u00e1 po predch\u00e1dzaj\u00facej reverznej transkripcii z izolovanej RNA. qRT-PCR umo\u017e\u0148uje presn\u00fa kvantifik\u00e1ciu PCR produktu v exponenci\u00e1lnej f\u00e1ze amplifika\u010dn\u00e9ho procesu detekciou vzrastu fluorescen\u010dn\u00e9ho sign\u00e1lu hydrolyza\u010dnej sondy. Intenzita fluorescencie je priamo \u00famern\u00e1 mno\u017estvu vznikaj\u00faceho produktu. Na presn\u00e9 ur\u010denie mno\u017estva produktu sl\u00fa\u017eia \u0161tandardy so zn\u00e1mym po\u010dtom k\u00f3pi\u00ed cDNA. Pomocou nich je mo\u017en\u00e9 \u00a0zostroji\u0165 kalibra\u010dn\u00fa krivku a presne ur\u010di\u0165 mno\u017estvo sledovan\u00fdch transkriptov v testovanej vzorke. Po\u010det \u00a0k\u00f3pi\u00ed cDNA sledovan\u00e9ho g\u00e9nu je normalizovan\u00fd k po\u010dtu k\u00f3pi\u00ed kontroln\u00e9ho g\u00e9nu (housekeeping g\u00e9n), v na\u0161om pr\u00edpade g\u00e9n A<\/em>B<\/em>L <\/em>(Abelson). Pomer po\u010dtu k\u00f3pi\u00ed f\u00fazneho g\u00e9nu B<\/em>C<\/em>R<\/em>–<\/em>A<\/em>B<\/em>L <\/em>k po\u010dtu k\u00f3pi\u00ed kontroln\u00e9ho g\u00e9nu A<\/em>B<\/em>L <\/em>n\u00e1m poskytne hodnotu NCN (normalizovan\u00fd po\u010det k\u00f3pi\u00ed f\u00fazneho g\u00e9nu). Molekulov\u00fa odpove\u010f stanovujeme v % pod\u013ea medzin\u00e1rodnej stupnice \u00a0IS (International Scale) vyn\u00e1soben\u00edm hodnoty NCN konverzn\u00fdm faktorom \u0161pecifick\u00fdm pre ka\u017ed\u00e9 laborat\u00f3rium.<\/p>\n
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V<\/strong>\u00fd<\/strong>sl<\/strong>e<\/strong>d<\/strong>k<\/strong>y<\/strong><\/p>\n
Kazuistika \u2013 pacientka 1<\/em><\/p>\n
Pacientke narodenej v roku 1984 bola diagnostikovan\u00e1 CML v chronickej f\u00e1ze v roku 2011. Po stanoven\u00ed diagn\u00f3zy CML bola za\u010dat\u00e1 lie\u010dba inhib\u00edtorom tyroz\u00ednkin\u00e1zy 1. l\u00ednie \u2013 imatinibom (Glivec\u00ae). Pacientka bola monitorovan\u00e1 v trojmesa\u010dn\u00fdch intervaloch pod\u013ea odpor\u00fa\u010dan\u00ed ELN, pri\u010dom po 6 mesiacoch od za\u010datia lie\u010dby dosiahla MMR (B<\/em>CR<\/em>–<\/em>A<\/em>B<\/em>L <\/em>\u2264 0,1 %) a pri n\u00e1slednej kontrole sme u\u017e f\u00fazny transkript B<\/em>CR<\/em>–<\/em>A<\/em>B<\/em>L \u00a0<\/em>na molekulovej \u00farovni nedetegovali. Po 32 mesiacoch \u00a0lie\u010dby bolo preru\u0161en\u00e9 u\u017e\u00edvanie TKI pre pl\u00e1novan\u00fa \u00a0graviditu. Pri \u010fal\u0161ej kontrole v 8. gesta\u010dnom t\u00fd\u017edni gravidity sme zaznamenali zv\u00fd\u0161en\u00fa hladinu B<\/em>CR<\/em>–<\/em>A<\/em>B<\/em>L\u00a0 <\/em>ako n\u00e1sledok preru\u0161enia lie\u010dby imatinibom. Gravidita sa vyv\u00edjala bez probl\u00e9mov, a\u017e k\u00fdm v 18. gesta\u010dnom \u00a0t\u00fd\u017edni nedo\u0161lo k zam\u013aknut\u00e9mu potratu. Ke\u010f\u017ee u pacientky do\u0161lo po\u010das obdobia vysadenia lie\u010dby k strate molekulovej remisie (B<\/em>CR<\/em>–<\/em>AB<\/em>L \u00a0<\/em>\u2265 0,1 %), bola u nej za\u010dat\u00e1 lie\u010dba s interfer\u00f3nom-\u03b1. Pacientke sa podarilo v priebehu p\u00e1r mesiacov znovu otehotnie\u0165, priebeh gravidity bol bez komplik\u00e1ci\u00ed a aj napriek lie\u010dbe \u00a0interfer\u00f3nom-\u03b1 do\u0161lo k strate cytogenetickej \u00a0aj hematologickej \u00a0remisie. V 39. gesta\u010dnom t\u00fd\u017edni sa pacientke narodilo zdrav\u00e9 die\u0165a a ihne\u010f po p\u00f4rode bola znovu za\u010dat\u00e1 lie\u010dba imatinibom, \u010do viedlo op\u00e4\u0165 k dosiahnutiu MMR (graf 1).<\/p>\n
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Kazuistika \u2013 pacientka 2<\/em><\/p>\n
Pacientka naroden\u00e1 v roku 1982 mala v roku 2008 diagnostikovan\u00fa chronick\u00fa f\u00e1zu CML a n\u00e1sledne sa u nej za\u010dala lie\u010dba imatinibom. Po kr\u00e1tkom \u010dase sa u nej prejavila rezistencia na lie\u010dbu \u00a0prvej l\u00ednie, \u010do viedlo k prechodu \u00a0na TKI 2. gener\u00e1cie \u2013 dasatinib (Sprycel\u00ae). Lie\u010dba viedla najsk\u00f4r k MMR a nesk\u00f4r aj k nedetekovate\u013enosti \u00a0B<\/em>C<\/em>R<\/em>–<\/em>A<\/em>BL \u00a0<\/em>na molekulovej \u00farovni. Po roku pacientka otehotnela a bola jej pozastaven\u00e1 lie\u010dba s TKI. Ke\u010f\u017ee tehotenstvo prebiehalo bez komplik\u00e1ci\u00ed, neu\u017e\u00edvala \u017eiadnu lie\u010dbu. Po p\u00f4rode jej bol op\u00e4\u0165 nasaden\u00fd dasatinib, na ktor\u00fd reagovala r\u00fdchlou\u00a0obnovou MMR. O rok pacientka znovu otehotnela, dasatinib bol vysaden\u00fd, za\u010dala\u00a0 sa lie\u010dba s interfer\u00f3nom-\u03b1. Po \u00faspe\u0161nom priebehu gravidity, av\u0161ak so stratou molekulovej, cytogenetickej \u00a0aj hematologickej \u00a0remisie sa pacientke narodilo druh\u00e9 zdrav\u00e9 die\u0165a. Po p\u00f4rode bol nasaden\u00fd dasatinib, a hoci do\u0161lo v kr\u00e1tkom \u010dase k obnove MMR, u pacientky nast\u00fapil po 3 mesiacoch molekulov\u00fd relaps ochorenia (graf 2).<\/p>\n
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Dis<\/strong>k<\/strong>usia<\/strong><\/p>\n
Akt\u00edvnou oblas\u0165ou s\u00fa\u010dasn\u00fdch v\u00fdskumov ost\u00e1va zodpoveda\u0165 ot\u00e1zku mo\u017enosti \u00a0pozastavenia lie\u010dby TKI pacientov \u00a0s CML, u ktor\u00fdch pretrv\u00e1va ve\u013ek\u00e1, pr\u00edpadne \u00a0a\u017e kompletn\u00e1 molekulov\u00e1 remisia (MR4,5 a MR5, t. j. pri MR4,5 hladina transkriptov B<\/em>C<\/em>R<\/em>–<\/em>A<\/em>BL \u00a0<\/em>\u2264 0,0032 % a pri MR5 hladina transkriptov B<\/em>CR<\/em>–<\/em>A<\/em>BL \u00a0<\/em>\u2264 0,001 %) aspo\u0148 2 roky. Rie\u0161enie \u00a0tohto \u00a0probl\u00e9mu \u00a0je zvl\u00e1\u0161\u0165 d\u00f4le\u017eit\u00e9 u pacientok s CML, ktor\u00fdch t\u00fa\u017ebou je ma\u0165 zdrav\u00e9 die\u0165a.<\/p>\n
Z na\u0161ich doteraj\u0161\u00edch pozorovan\u00ed je zrejm\u00e9, \u017ee stabiln\u00e1 MMR (> 2 roky) nie je v\u017edy z\u00e1rukou bezpe\u010dn\u00e9ho zastavenia lie\u010dby s TKI. U oboch pacientok do\u0161lo v pomerne \u00a0kr\u00e1tkom \u010dase k strate molekulovej a n\u00e1sledne i cytogenetickej a hematologickej odpovede, ktor\u00fa sa nepodarilo obnovi\u0165 ani u\u017e\u00edvan\u00edm interfer\u00f3nu-\u03b1. Po op\u00e4tovnom nasaden\u00ed TKI u pacientky 1 a 2 do\u0161lo v kr\u00e1tkom \u010dase k obnove MMR, av\u0161ak u pacientky 2 nastala jej strata. Tento v\u00fdsledok m\u00f4\u017ee s\u00favisie\u0165 s t\u00fdm, \u017ee interval trvania MMR pred graviditou bol menej ako 2 roky, ale aj s t\u00fdm, \u017ee pozastavenie lie\u010dby s TKI bolo pr\u00edli\u0161 dlh\u00e9. Pod\u013ea dostupn\u00fdch klinick\u00fdch pozorovan\u00ed toti\u017e nie je v s\u00fa\u010dasnosti mo\u017en\u00e9 jednozna\u010dne poveda\u0165, ak\u00e1 je \u00fanosn\u00e1 d\u013a\u017eka preru\u0161enia lie\u010dby s TKI bez toho, aby u pacientov \u00a0do\u0161lo k progresii ochorenia.<\/p>\n
 <\/p>\n
Z<\/strong>\u00e1<\/strong>ver<\/strong><\/p>\n
Mana\u017ement lie\u010dby CML po\u010das tehotenstva je stredobodom z\u00e1ujmu viacer\u00fdch pracovn\u00fdch \u00a0vedeck\u00fdch skup\u00edn a je ve\u013ekou v\u00fdzvou nielen pre hematol\u00f3gov a gynekol\u00f3gov, ale aj pre samotn\u00fa pacientku, ke\u010f\u017ee v s\u00fa\u010dasnosti nie je dostatok inform\u00e1ci\u00ed o vplyve pozastavenia lie\u010dby s TKI po\u010das gravidity na udr\u017eanie dostato\u010dne hlbokej molekulovej remisie. Molekulov\u00e9 sledovanie tehotn\u00fdch pacientok s CML, poskytuj\u00face \u00fadaje o hladine transkriptov f\u00faznych g\u00e9nov BCR-ABL \u00a0<\/em>by malo by\u0165 samozrejmos\u0165ou v \u010dastej\u0161\u00edch intervaloch ne\u017e 3 mesiace (napr\u00edklad 1-kr\u00e1t\/mesiac).<\/p>\n
 <\/p>\n
L<\/strong>it<\/strong>e<\/strong>ra<\/strong>t<\/strong>\u00fa<\/strong>ra<\/strong><\/p>\n
1<\/strong>. <\/strong>Rowley JD. Letter: A new consistent chromosomal abnormality in chronic myelogenous leu- kaemia identified by quinacrine fluorescence and Giemsa staining. N<\/em>a<\/em>tu<\/em>r<\/em>e<\/em>. 1973;243:290\u2013293.<\/p>\n
2<\/strong>. <\/strong>Druker BJ, Sawyers CL, Capdeville R, et al. Chronic myelogenous leukemia. Hem<\/em>atology <\/em>Am\u00a0<\/em>S<\/em>o<\/em>c Hematol Educ Program. <\/em>2001;87\u2013112.<\/p>\n
3<\/strong>. <\/strong>Baccarani M, Cortes J, Pane F, et al. European LeukemiaNet. Chronic myeloid leukemia: an update of concepts and management recommendation of European LeukemiaNet. J Clin Oncol. <\/em>2009;27(35):6041\u20136051.<\/p>\n
4<\/strong>. <\/strong>Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib \u00a0in newly \u00a0diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med<\/em>. 2010;362:2260\u20132270.<\/p>\n
5<\/strong>. <\/strong>Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. <\/em>2010;362:2251\u20132259.<\/p>\n
6<\/strong>. <\/strong>Pye SM, Cortes J, Ault P, et al. The effects of imatinib on pregnancy outcome. Bl<\/em>oo<\/em>d<\/em>.\u00a0<\/em>2008;111:5505\u20135508.<\/p>\n
7<\/strong>. <\/strong>Apperley CML in pregnancy and childhood. B<\/em>es<\/em>t Pract Res Clin Haematol. <\/em>2009;22:455\u2013474.<\/p>\n
8<\/strong>. <\/strong>Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia. Bl<\/em>oo<\/em>d<\/em>. <\/em>2013;122:872\u201388<\/p>\n
9<\/strong>. <\/strong>Cortes J, Talpaz M, O\u2019Brian S, et al. Molecular responses in patients with chronic myelogenous leukemia in chronic phase treated with imatinib mesylate. Clin Cancer <\/em>Re<\/em>s<\/em>. 2005;11:3425\u20133432.<\/p>\n
1<\/strong>0<\/strong>. <\/strong>Palandri F, Lacobucci I, Soverini S, et al. Treatment of philadelphia-positive chronic myeloid leukemia with imatinib: importance of a stable molecular \u00a0response. Cli<\/em>n Cancer Res.\u00a0<\/em>2009;15:1059\u20131063.<\/p>\n
1<\/strong>1<\/strong>. <\/strong>Mahon FX, Rea D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. <\/em>2010;11:1029\u20131035.<\/p>\n
1<\/strong>2<\/strong>. <\/strong>Faderl S, Talpaz M, Estrov Z, et al. The biology of chronic myeloid leukemia. N Engl J Med.\u00a0<\/em>1999;341(3):164\u2013172.<\/p>\n
1<\/strong>3<\/strong>. <\/strong>Koh LP, Kanagalingam D. Pregnancies in patient with chronic myeloid leukemia in the era of imatinib. I<\/em>n<\/em>t J Hematol. <\/em>2006;84:459\u2013462.<\/p>\n
 <\/p>\n
 <\/p>\n","protected":false},"excerpt":{"rendered":"
*All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf attachment at the end of the paper.   \u00davod Chronick\u00e1 myelocytov\u00e1 leuk\u00e9mia (CML) je klon\u00e1lne myeloproliferat\u00edvne ochorenie vych\u00e1dzaj\u00face z transformovanej kme\u0148ovej pluripotentnej hematopoetickej bunky, pri ktorom dominuje prolifer\u00e1cia granulopo\u00e9zy. Typickou pre t\u00fato diagn\u00f3zu \u00a0je recipro\u010dn\u00e1 \u00a0translok\u00e1cia dlh\u00fdch<\/p>\n","protected":false},"author":7,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_mi_skip_tracking":false,"footnotes":""},"categories":[290],"tags":[657,659,660,658],"class_list":["post-1066","post","type-post","status-publish","format-standard","hentry","category-genetics","tag-chronic-myeloid-leukemia","tag-molecular-response","tag-pregnancy","tag-tyrosine-kinase-inhibitors","typ_clanku-original-work"],"acf":{"abstrakt":"
Introduction:\u00a0<\/strong>In the era of tyrosine kinase inhibitors (TKI), treatment of patients with chronic myeloid leukemia (CML) during pregnancy represents an important clinical challenge not only from the perspective of a hematologist, but also from the perspective of a clinical geneticist who performs a laboratory analysis. The introduction of TKI into clinical practice improved the prognosis of patients with CML to an extent allowing them to live a full-valued life, not excluding plans of pregnancy in female CML patients. According to current clinical recommendations, in view of potential teratogenic effects of TKI, planned pregnancy with discontinuation of treatment before pregnancy is recommended.<\/p>\n
Cases:<\/strong> The following are examples of 2 female CML patients with a different interval duration of stable MMR before pregnancy, in whom TKI treatment was interrupted.<\/p>\n
Results:<\/strong> Reported cases point to importance of stable MMR before planned pregnancy with discontinuation of TKI treatment.<\/p>\n
Conclusion:<\/strong> Pregnancy planning in female patients with CML is possible after achieving major molecular response with persistence for at least 2 years. During pregnancy, regular measurement of the complete blood count with the leukocyte differential count is recommended, while periodic molecular detection of BCR-ABL gene is essential.<\/p>\n
 <\/p>\n
Key words:<\/strong> chronic myeloid leukemia, tyrosine kinase inhibitors, molecular response, pregnancy<\/p>\n","casopis":[{"ID":991,"post_author":"7","post_date":"2017-02-01 09:43:42","post_date_gmt":"2017-02-01 08:43:42","post_content":"
    \r\n \t
  • Pulmonary aspergillosis<\/li>\r\n \t
  • Infections caused by cytomegalovirus \u2013 diagnosis and therapy<\/li>\r\n \t
  • Long-term molecular remission as a precondition for successful pregnancy in patients with chronic myelocyte leukemia<\/li>\r\n \t
  • Chromosome 11 aberrations in a patient with acute myeloid leukemia \u2013 a case study<\/li>\r\n \t
  • New biomarkers in diagnosing IgA nephropathy<\/li>\r\n<\/ul>","post_title":"newslab","post_excerpt":"","post_status":"publish","comment_status":"closed","ping_status":"closed","post_password":"","post_name":"newslab-2016-02","to_ping":"","pinged":"","post_modified":"2017-08-16 21:36:48","post_modified_gmt":"2017-08-16 19:36:48","post_content_filtered":"","post_parent":0,"guid":"http:\/\/www.newslab.sk\/casopis\/newslab-2016-02\/","menu_order":0,"post_type":"casopis","post_mime_type":"","comment_count":"0","filter":"raw"}],"strana":"109","upload_clanok":{"ID":1067,"id":1067,"title":"Newslab_2_2016_Dlhodob\u00e1 molekulov\u00e1 remisia ako","filename":"Newslab_2_2016_Dlhodob\u00e1-molekulov\u00e1-remisia-ako.pdf","filesize":638808,"url":"https:\/\/www.newslab.sk\/wp-content\/uploads\/2017\/01\/Newslab_2_2016_Dlhodob\u00e1-molekulov\u00e1-remisia-ako.pdf","link":"https:\/\/www.newslab.sk\/en\/long-lasting-molecular-remission-as-a-precondition-for-successful-pregnancy-in-female-patients-with-chronic-myeloid-leukemia\/newslab_2_2016_dlhodoba-molekulova-remisia-ako\/","alt":"","author":"7","description":"","caption":"","name":"newslab_2_2016_dlhodoba-molekulova-remisia-ako","status":"inherit","uploaded_to":1066,"date":"2017-02-01 19:35:15","modified":"2017-02-01 19:35:15","menu_order":0,"mime_type":"application\/pdf","type":"application","subtype":"pdf","icon":"https:\/\/www.newslab.sk\/wp-includes\/images\/media\/document.png"}},"_links":{"self":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts\/1066","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/users\/7"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/comments?post=1066"}],"version-history":[{"count":0,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts\/1066\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/media?parent=1066"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/categories?post=1066"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/tags?post=1066"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}