Clinical Features ntawm mob raum mob hauv cov neeg mob tau txais Dabrafenib Thiab Trametinib Ⅱ
Dec 01, 2023
TSEEM CEEB
Peb tau txheeb xyuas 266 tus neeg mob uas tau txais dabrafenib ntawm 2010 thiab 2019 nyob rau hauv Mass General Brigham kev noj qab haus huv network, uas suav nrog cov neeg mob pom ntawm ob lub chaw loj (Massachusetts General Hospital Cancer Center thiab Dana Farber Cancer Institute) hauv Boston, MA, USA. Tom qab siv peb cov txheej txheem cais tawm, 199 tus neeg mob tau suav nrog hauv kev tshuaj xyuas. Yog vim li cas rau kev cais tawm yog cov ntaub ntawv tsis txaus los tsim hnub pib ntawm dabrafenib thiab trametinib (n ¼ 33), tsis muaj creatinine hauv paus (n ¼ 26), tsis muaj creatinine rov qab tom qab pib dabrafenib thiab trametinib (n ¼ 7) lossis tau txais kev lim ntshav thaum pib kho (n ¼ 1). Cov neeg mob tau ua raws li qhov nruab nrab ntawm 680 hnub (SD 692) thiab qhov 6- thiab 12-hloov ciaj sia taus yog 81 thiab 54%, feem.
CISTANCHE DIETARY SUPPLEMENT SEXUAL ENHANCEMENT PHENYLETHANOID GLYCOSIDES 75% ECHINACOSIDE 30% ACTEOSIDE 12%
Cov yam ntxwv ntawm lub hauv paus
Lub hnub nyoog nruab nrab yog 59 xyoo (SD 16), 56% yog txiv neej, 94% yog neeg dawb, 10% muaj ntshav qab zib mellitus, 57% muaj ntshav siab thiab 30% muaj kab mob siab ntawm lub hauv paus ( Table 1). Feem ntau (75%) tau txais dabrafenib thiab trametinib los kho melanoma. Feem ntau (95%) tau pib siv cov tshuaj dabrafenib 150 mg ob zaug ib hnub thiab trametinib 2 mg txhua hnub. Tag nrho ntawm 29% muaj ICI tsis ntev los no los yog concurrent. Qhov nruab nrab lub hauv paus creatinine yog 0.9 mg / dL (SD 0.2) thiab 20 tus neeg mob (10%) muaj kab mob raum ntev (eGFR<60 mL/min/1.73 m2 ) at baseline. Overall, 42 patients (21%) experienced AKI at a mean of 141 days (SD 116) after starting dabrafenib. AKI Stage 1 (creatinine >1.5–2 times baseline) was seen in 21 patients (50%), AKI Stage 2 (creatinine >2–3 times baseline) in 13 patients (31%) and AKI Stage 3 (creatinine >3 zaug hauv paus lossis xav tau kev lim ntshav) hauv 8 tus neeg mob (19%).
Etiology thiab kwv yees ntawm AKI
Los ntawm daim ntawv qhia ntxaws ntxaws ntawm 42 tus neeg mob nrog AKI, peb nrhiav pom tseeb lwm qhov ua rau AKI hauv 32 tus neeg mob (Daim duab 1). Txawm li cas los xij, 10 tus neeg mob (5% ntawm tag nrho pawg, 24% ntawm cov neeg mob AKI) tau ntsib AKI hauv cov ntsiab lus ntawm dabrafenib thiab trametinib-induced febrile syndromes uas yog mob febrile mob; Txhua tus tau ntsib kev ua npaws, ua daus no thiab mob plab hnyuv (xws li xeev siab / ntuav / raws plab). Cov ntaub ntawv ntxiv, Table S1 piav qhia qhov kev tshawb pom hauv cov xwm txheej no. Yim tus neeg mob (80%) tau nce siab enzymes, ob (20%) muaj cov pob liab liab tshiab thiab tsis muaj eosinophilia. Urinalysis tau ua nyob rau hauv yim tus neeg mob; Tsuas yog ob leeg muaj leukocyturia thiab ib tus muaj hematuria (Cov ntaub ntawv ntxiv, Table S1). Feem ntau txhim kho sai nrog kev tshem tawm ntawm dabrafenib thiab trametinib. Plaub tus neeg mob (40%) tau txais corticosteroids (prednisone 10 mg txhua hnub lossis sib npaug) vim muaj cov tsos mob tsis tu ncua. Qhov hnyav ntawm AKI hauv 10 tus neeg mob no yog raws li hauv qab no: tsib tus neeg mob tau Theem 1 AKI, peb muaj theem 2 AKI thiab ob leeg muaj Theem 3 AKI. Ib nrab tau mus pw hauv tsev kho mob thaum lub sijhawm AKI thiab ib nrab yog cov neeg mob sab nraud. Rau ntawm 10 tus neeg mob tau rov hais dua nrog dabrafenib thiab trametinib ntawm qis dua; 2 ntawm 6 (33%) muaj AKI (cov ntaub ntawv ntxiv, Table S1).
FIGURE 1: Etiology and severity of AKI. Chart review of each case of AKI uncovered the following etiologies, adjudicated by two nephrologists. Dabrafenib and trametinib–associated AKI [n ¼ 10 (24%)] occurred in patients manifesting systemic symptoms of fever, rash and liver function test abnormalities attributed to dabrafenib–trametinib toxicity by their primary oncologist. Prerenal azotemia [n ¼ 17 (40%)] occurred due to dehydration (poor oral intake, diarrhea and vomiting) that resolved within 48 h of supportive care. Infection-associated ATN [n ¼ 4 (10%)] lasted >48 teev txawm tias muaj kev txhawb nqa thiab hauv txhua kis tau cuam tshuam nrog cov ntaub ntawv kis kab mob / sepsis. AKI vim yog lwm cov tshuaj nephrotoxic anticancer [n ¼ 3 (7%)] raug ntaus nqi los ntawm vemurafenib (n ¼ 1) lossis pembrolizumab siv (n ¼ 2). AKI cuam tshuam nrog cov kab mob davhlau ya nyob twg [n ¼ 8 (19%)] tshwm sim thaum lub sijhawm sau npe hauv tsev kho mob lossis tuag.
Lwm yam etiologies ntawm AKI suav nrog prerenal azotemia (40% ntawm AKI), sepsis-txog ATN (10%), nephrotoxicity vim yog lwm cov tshuaj tiv thaiv kab mob hauv 7% (xws li pembrolizumab hauv 2 lossis vemurafenib hauv 1) thiab AKI uas tshwm sim ua ib feem. ntawm lub davhlau ya nyob twg poob (19%). Kev tawg ntawm AKI etiologies thiab theem hnyav yog qhia hauv daim duab 3.
Tus qauv logistic regression univariable qhia nyob rau hauv Table 1 qhia tau hais tias preexisting daim siab kab mob tsuas yog tus yam ntxwv uas muaj ntau dua nyob rau hauv cov neeg mob uas tsim AKI piv nrog cov neeg uas tsis. Hauv cov qauv sib txawv uas kuj suav nrog hnub nyoog thiab poj niam txiv neej, kab mob siab ua ntej tseem tau kwv yees ntawm AKI, nrog kev hloov kho qhov sib txawv ntawm 3.13 (95% kev ntseeg siab lub sijhawm 1.55–6.35; P < 0.01) (Cov ntaub ntawv ntxiv, Table S2). Kev siv Proton twj tso kua mis inhibitor (PPI) tau siab dua hauv cov pab pawg uas tsim AKI, tab sis qhov no tsis yog qhov tseem ceeb. Lub hauv paus ua haujlwm ntawm lub raum thiab kev noj ib txhij ntawm lwm cov tshuaj cuam tshuam nrog AIN tsis cuam tshuam nrog AKI. Peb nco ntsoov tias peb lub ntsiab lus ntawm kev siv tshuaj hauv paus, uas tau khaws cov ntaub ntawv sau tshuaj thiab tsis siv hauv khw muag khoom, yuav muaj kev kwv yees tsis zoo ntawm kev siv cov tshuaj uas tsis yog tshuaj steroidal anti-inflammatory (NSAIDs). Kev tshuaj xyuas ntawm 10 qhov xwm txheej ntawm dabrafenib thiab trametinib-induced AKI tau qhia tias ib nrab tau qhia txog kev noj NSAIDs los kho kub taub hau thaum lub sijhawm kuaj AKI (Cov ntaub ntawv ntxiv, Table S1).
We identified one patient with biopsy-proven AIN. He was a 70-year-old man with a history of Stage IIIA malignant melanoma who presented to the hospital with fever, elevated creatinine and liver function test abnormalities. He had been started on dabrafenib and trametinib 5 months prior to presentation after undergoing a wide excision and axillary lymph node removal. His treatment was complicated by recurrent fevers that worsened despite dose adjustments and treatment holidays (Figure 2). His last dose of dabrafenib and trametinib was 10 days prior to presentation and his baseline creatinine was 1.1 mg/dL at that time. He endorsed rare ibuprofen use, with the last dose taken >1 lub lis piam ua ntej nkag. Hauv nws lub chaw ua haujlwm ntawm tus kws kho mob oncologist, kev sim kuaj pom tau pom cov ntshav siab creatinine ntawm 2.2 mg / dL thiab kuaj lub siab ua haujlwm tsis zoo (alanine aminotransferase 151 U / L, aspartate transferase 127 U / L, alkaline phosphatase 652 U / L, tag nrho bilirubin {{6} }.5 mg/dL thiab albumin 3.5 g/dL). Nws cov zis sodium yog 99 mg / dL thiab cov zis tso zis protein: creatinine piv yog 0.25 g / g creatinine (ib txwm muaj.<0.15 g/g). Urine sediment microscopy showed rare leukocyte casts. Complete blood count (CBC) with differential was only remarkable for mild lymphopenia and normocytic anemia with hemoglobin of 10.4 g/dL; eosinophilia was not present. When his creatinine did not improve with intravenous normal saline administration, he was admitted to the hospital and underwent kidney biopsy. The biopsy showed diffuse interstitial inflammation involving up to 70% of the cortex, associated with edema, granuloma formation, focal tubular rupture and severe tubulitis (Figure 3). He has treated with intravenous methylprednisolone 500 mg for 2 days, then started on prednisone 60 mg daily, which was tapered by 10 mg every 3 days for an 18-day total course of corticosteroids. Serum creatinine improved to 1.3 mg/dL within the first week of treatment and remained at 1.2 mg/dL at his last follow-up, >6 lub lis piam tom qab ua tiav cov tshuaj steroids (Daim duab 2). Nws lub siab ua haujlwm kuaj kuj normalized nrog corticosteroids. Nws txoj kev kho adjuvant tau raug txiav mus tas li tab sis nws tseem nyob hauv kev zam txim tiav.
Daim duab 2: Kev kho mob ntawm tus neeg mob nrog AIN. Tus neeg mob pib koob tshuaj ntawm dabrafenib-trametinib. Nws pib muaj kev rov tshwm sim ntawm kub taub hau thiab ua daus no pib 1 lub lis piam tom qab pib ntawm dabrafenib-trametinib uas ua rau muaj kev cuam tshuam ntawm koob tshuaj thiab txo qis. Nws cov creatinine tau nce ntxiv txawm tias 10 hnub ntawm kev kho qhov txiav tawm. Nws tau mus pw hauv tsev kho mob, muab cov dej tso rau hauv cov hlab ntsha thiab ua rau lub raum biopsy uas pom tias granulomatous interstitial nephritis. Nws tau txais ob koob tshuaj methylprednisolone 500 mg thiab tau tawm nrog cov tshuaj prednisone sai (pib 60 mg thiab tapered los ntawm 10 mg txhua 3 hnub).
Kev tshuaj xyuas ntawm FAERS cov ntaub ntawv qhia tag nrho ntawm 250 lub raum cuam tshuam txog cov xwm txheej tsis zoo hauv cov neeg mob ntawm dabrafenib (Cov ntaub ntawv ntxiv, Table S3). Plaub caug feem pua ntawm cov xwm txheej tsis zoo tau sau tseg hauv cov txiv neej thaum 32% tau sau tseg hauv cov poj niam (28% tsis paub). Lub hnub nyoog nruab nrab ntawm cov xwm txheej tsis zoo yog 67 xyoo (SD 11) rau cov txiv neej thiab 64 xyoo (SD 23) rau poj niam. 'Lub raum raug mob' yog qhov tshwm sim tsis zoo rau lub raum, sau tseg hauv 115 tus neeg mob. Lwm cov xwm txheej cuam tshuam rau lub raum muaj xws li hyponatremia (26%) thiab hypokalemia (16%).
Kev sib tham
Hauv ib pawg ntawm ze li ntawm 200 tus neeg mob tau txais dabrafenib thiab trametinib, peb pom tias, zoo li lwm yam kev kho mob BRAF-MEK, AKI yog ib txwm muaj, tshwm sim hauv 21% hauv thawj xyoo. Txawm li cas los xij, peb pom tias hauv 10 tus neeg mob (5% ntawm tag nrho pawg), AKI tau tshwm sim hauv qhov teeb meem ntawm cov mob febrile mob hnyav vim yog dabrafenib thiab trametinib; Qhov no yog qhov tshwj xeeb thaum piv nrog cov lus ceeb toom ntawm AKI tom qab vemurafenib-cobimetinib thiab encorafenib-binimitinib. Cov neeg mob tau nthuav tawm cov tsos mob ntawm plab hnyuv thiab lub siab ua haujlwm kuaj qhov txawv txav thiab cov neeg tsawg kuj muaj pob liab liab lossis kev puas siab puas ntsws hloov. Tus nqi ntawm dabrafenib thiab trametinib-koom nrog AKI hauv qhov kev tshawb fawb hauv ntiaj teb no yog siab dua li tau hais tseg hauv kev sim ua ntej thiab cov ntaub ntawv sau tshuaj [9, 10]. Txawm hais tias feem ntau ntawm cov teeb meem daws tau nrog kev kho mob, ntau tus neeg mob xav tau corticosteroids los txo qhov kub taub hau thiab daws AKI. Feem ntau cov neeg mob tau rov ua dua nrog dabrafenib thiab trametinib, thiab txawm hais tias qee tus tau rov ua dua ntawm febrile syndrome thiab AKI, ntau tus tuaj yeem zam qhov txo qis dua yam tsis muaj AKI. Peb kuj tau txheeb xyuas qhov xwm txheej thib ob ntawm kev mob qog nqaij hlav loj-pov thawj AIN tshwm sim tom qab dabrafenib-trametinib. Txawm hais tias qhov tseeb tias AIN tau teev npe raws li qhov tshwm sim tsis zoo hauv cov ntaub ntawv sau tshuaj rau dabrafenib, qhov xwm txheej tseeb tsis meej, vim tsuas yog ib qho xwm txheej ua ntej tau tshaj tawm hauv cov ntaub ntawv [11]. Cov koob no qhia tias qhov xwm txheej ntawm AIN yog<1%, although no other patients with dabrafenib and trametinib–induced AKI in this series underwent kidney biopsy, thus AIN may have been underdiagnosed.
Lwm cov BRAF inhibitors thiab BRAF-MEK ob peb ua ke tau txuam nrog AKI [3, 4, 16–19]. Cov ntaub ntawv ntawm biopsy-proven interstitial fibrosis thiab mob focal tubular puas tau raug tshaj tawm nrog vemurafenib [3, 19, 20]. Qhov tshwm sim ntawm AKI af ter vemurafenib siv (txhais tau tias yog 1.5-fold nce hauv creatinine los ntawm lub hauv paus) yog 60% hauv 74- neeg mob series [19]. Qhov tshwm sim ntawm AKI hauv cov neeg mob tau txais BRAF-MEK kev sib xyaw ua ke yog qis dua, xws li 24 txog 26% hauv cov neeg mob kho nrog vemurafenib thiab cobimitinib lossis encorafenib thiab binimetinib [4, 21]. Ib txoj kev tshawb nrhiav pom tias cov txheej txheem ntawm kev nce creatinine hauv cov neeg mob tau txais vemurafenib tuaj yeem cuam tshuam rau inhibited tubular secretion ntawm creatinine nrog rau lub raum ua haujlwm tsis zoo; ob tus neeg mob hauv cov koob no tau ua tiav biopsies qhia ncaj qha raum tubular epithelial cell raug mob [22]. Nyob rau hauv ib qho tsis ntev los no ntawm AKI tom qab encorafenib thiab binimetinib, cov neeg mob tau pom cov tsos mob ntawm lub raum tubular raug mob. Tsis muaj ib tus neeg mob AKI tau ua npaws, pob khaus lossis cov tsos mob ntawm AIN, tab sis tsis muaj biopsied [4]. Lwm cov ntaub ntawv qhia tau hais tias cov kab mob glomerular yuav tshwm sim tom qab BRAF-MEK inhibition, tab sis qhov no zoo li tsis tshua muaj [16, 23]. Perisco et al. [23] kuaj cov nyhuv ntawm dabrafenib thiab trametinib ntawm kab lis kev cai tib neeg podocytes, qhia dabrafenib cuam tshuam nrog thiab downregulates PLCe1, ib tug slit diaphragm-kawg protein, thiab kuj downregulated nephrin thiab nce permeability ntawm podocyte monolayers. Txawm li cas los xij, hauv peb txoj kev tshawb fawb, cov neeg mob uas muaj dabrafenib thiab trametinib-koom nrog AKI tsis muaj proteinuria tseem ceeb; tsuas yog ib rooj plaub muaj 2þ proteinuria ntawm dipstick.
Febrile syndromes that share overlapping features with cytokine release syndrome are being recognized more commonly after targeted cancer therapies, particularly when given after ICIs [24, 25]. It is important to note that 7 of 10 of our cases of dabrafenib and trametinib–associated AKI did not have concurrent exposure to ICIs (Supplementary data, Table S1). The FDA prescribing information recommends withholding dabrafenib and trametinib for fever >104 F lossis rau qhov mob febrile hnyav lossis kub taub hau nrog hypotension, nruj lossis txias, lub cev qhuav dej lossis AKI [9, 10]. Ua tib zoo saib xyuas cov ntshav creatinine thaum lub sijhawm muaj pyrexia hnyav kuj raug pom zoo.
The mechanism of AIN after dabrafenib and trametinib is unclear. There is considerable debate about whether corticosteroids should be used in AIN versus simply withholding the offending agent [26–28]. We note that in this case, the patient's serum creatinine continued to rise for >10 hnub uas tsis tau txais dabrafenib thiab trametinib txawm tias muaj kev txhawb nqa nrog kev tso dej hauv cov hlab ntsha. Lub raum biopsy pom qhov mob hnyav, ua haujlwm tubulitis nrog kev tsim granuloma, yog li corticosteroids tau tswj hwm. Nws cov creatinine tau txhim kho sai sai thaum nws tau txais methylprednisolone thiab nws tsis muaj AKI rov tshwm sim tom qab ua tiav 18-hnub chav kawm ntawm prednisone. Qhov no yog qhov sib piv rau yav dhau los daim ntawv tshaj tawm ntawm biopsy-pov thawj AIN tom qab dabrafenib thiab trametinib hauv cov ntaub ntawv, qhov twg tus neeg mob tau rov ua dua AKI tom qab corticosteroids raug txiav tawm [11]. Vim tias muaj kub taub hau thiab txias txias uas yuav tshwm sim los ntawm dabrafenib thiab trametinib, cov neeg mob feem ntau raug qhia kom kho tus mob ua npaws nrog alternating acetaminophen thiab NSAIDs. NSAIDs tuaj yeem ua kom muaj zog prerenal azotemia thiab cuam tshuam nrog AIN thiab ib nrab ntawm cov neeg mob AKI tsis ntev los no tau tshaj tawm NSAID siv [29, 30]. Kev sib raug zoo ntawm AIN-provoking concomitant tshuaj raws li qhov muaj feem cuam tshuam rau lub raum tiv thaiv kab mob cuam tshuam rau cov neeg mob kho nrog ICIs kuj tau tshaj tawm [31]. Nyob rau hauv cov ntaub ntawv ntawm cov ntaub ntawv, dabrafenib tau piav raws li ib tug muaj peev xwm ua rau lub reactivation ntawm preexisting autoimmune kab mob, xws li dermatomyositis thiab antineutrophil cytoplasmic anti-body (ANCA)-associated granulomatosis nrog polyangiitis [32, 33]. Cov txheej txheem tom qab xws li dabrafenib cuam tshuam txog kev tiv thaiv kab mob tsis tau tsim. Nws tsis paub yog tias dabrafenib-mediated AIN thiab cov kab mob autoimmune tau hais los saum toj no rov ua raws li tib txoj hauv kev thiab xav tau kev tshawb fawb ntxiv hauv thaj chaw no. ANCA tsis tau ntsuas nyob rau hauv ib qho ntawm peb kis ntawm dabrafenib-koom nrog AKI.
While most of the patients (75%) in our series had melanoma, dabrafenib and trametinib are also approved by the FDA for the treatment of BRAFV600E-mutated non–small cell lung carcinoma and anaplastic thyroid carcinoma. These agents are also under clinical study in >80 kev sim tshuaj [34]. Vim muaj tsawg tsawg ntawm lwm cov qog nqaij hlav hauv peb cov pej xeem, nws nyuaj rau kev txiav txim siab seb dabrafenib thiab trametinib-txog AKI yuav nyob ntawm seb hom mob qog noj ntshav lossis theem ntawm tus kab mob. Kev sim tshuaj ntsuam xyuas yav tom ntej ntawm BRAF-MEK inhibition yuav tsum suav nrog cov lus piav qhia ntawm cov qog nqaij hlav thiab kev soj ntsuam ntev ntawm lub raum ua haujlwm txhawm rau txheeb xyuas qhov sib txawv ntawm AKI hla cov qog noj ntshav thiab nrog rau kev kho mob sib txawv.
Peb txoj kev tshawb fawb muaj ntau yam kev txwv. Ua ntej, qhov no yog cov neeg dawb feem ntau tau txais los ntawm ib lub koom haum saib xyuas kev noj qab haus huv, uas txwv tsis pub muaj peev xwm. Tsis tas li ntawd, nws muaj peev xwm hais tias cov neeg mob tau kuaj xyuas hauv tsev kho mob sab nraud peb lub network kev noj qab haus huv, ua rau muaj qhov tsis txaus ntseeg ntawm qhov zaus ntawm AKI. Peb tsuas suav nrog cov neeg mob uas muaj tsawg kawg yog ib qho creatinine ntsuas nyob rau hauv 12- lub hlis tom qab los xyuas kom meej tias cov neeg mob tau txais feem ntau ntawm lawv cov kev saib xyuas sab nraud peb cov kev kho mob tsis suav nrog hauv kev tshuaj ntsuam. Kev sau cov ntaub ntawv rov qab ua rau muaj kev txwv tsis pub muaj kev kho mob ntawm qee kis ntawm AKI thiab yog li peb yuav tsum tau tso siab rau cov ntaub ntawv muaj nyob hauv chav kuaj mob thiab kev soj ntsuam kev soj ntsuam thaum lub sijhawm tshwm sim. Txawm li cas los xij, kev tshuaj xyuas ntawm txhua rooj plaub los ntawm ob tus kws kho mob nephrologist yog lub zog. Qhov tseeb tias tsuas yog ib tus neeg mob tau txais lub raum biopsy txwv peb lub peev xwm los txiav txim siab qhov xwm txheej ntawm AIN nrog dabrafenib thiab trametinib.
Kev paub txog AKI kev pheej hmoo thiab kev kho mob ntawm AKI yog qhov tseem ceeb hauv cov neeg mob uas tau txais kev kho mob qog noj ntshav vim AKI tsis zoo cuam tshuam rau kev mob qog noj ntshav [35, 36]. Tsis tas li ntawd, AKI tuaj yeem ua rau muaj kev cuam tshuam kev kho mob thiab txwv tsis pub nkag mus rau lwm txoj kev kho mob qog noj ntshav lossis kev sim tshuaj kho mob, ntau yam uas txwv lossis tsis tau kawm hauv cov neeg mob uas txo qis hauv lub raum [37, 38]. Cov kws kho mob yuav tsum paub tias AKI feem ntau tshwm sim hauv cov neeg mob tau txais dabrafenib thiab trametinib. Kev saib xyuas lub raum ua haujlwm (cov ntshav creatinine thiab urinalysis) yuav tsum yog ib feem ntawm kev ntsuas tus qauv hauv cov neeg mob tau txais cov tshuaj no. AKI tej zaum yuav muaj kev cuam tshuam ncaj qha lossis tsis ncaj ntawm dabrafenib thiab trametinib siv. Hauv cov neeg mob uas AKI tsis daws sai sai nrog kev txiav tawm ntawm kev kho mob thiab kev txhawb nqa, cov kws kho mob yuav tsum xav txog kev kuaj mob raum txhawm rau ntsuas yog tias muaj AIN tam sim no.
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