RELAPS NHL TEDAVİSİNDE Tx ÖNCESİ YENİ TEDAVİLER Dr. Ali Uğur URAL

Mato R et al, Oncologist, 2012

%>40’u tedaviye cevap verir 2011’de 66.360 yeni NHL vakası %85’i B-hücreli %28’i DLCL %10’u refrakter %>40’u tedaviye cevap verir 2-5 yıl içinde relaps Kemik iliği, Testis ve Sinus tutulumu olanlar ile Yüksek IPI skoru bcl-2 aşırı ifadesi olanlar

Prichard M et al, Expert Opin Pharmacother, 2009

Relaps NHL’de nakil öncesi tedavide… Yeni kombinasyonlar Monoklonal antikorlar Radioimmunoterapi Yeni ajanlar (Pixantrone, Bendamustine, Bevacizumab…..) 6

NHL tedavisinde yeni hedefler 7

Prichard M et al, Expert Opin Pharmacother, 2009 CR %24; +R ile CR %53 CR %37; +R ile CR %45 Salvage KT’ler CR %24-27 ORR %62; +R ile CR %82 ORR %48; CR %21 Prichard M et al, Expert Opin Pharmacother, 2009

NHL’de monoklonal antikorlar kullanılır. Çünkü…. Mevcut tedavilerle yetersiz kürabilite vardır KT’lerden sonra MRD tedavisi prognozu düzeltebilir Antikorlar, sitostatik ilaçlardan daha özgündür Antikorlar daha az toksiktir Antikorların KT’lerden farklı etki mekanizmaları vardır

Rituximab: Fare/insan chimeric anti- CD20 monoklonal antikoru Fare değişken yöreleri normal / malign B-hücrelerindeki CD20’ye bağlanır İnsan K sabit yöreleri İnsan IgG1 Fc domaini İnsan efektör mekanizmaları ile etkileşir Düşük immunogenicity 10

Direkt apoptozis indüksiyonu Anti-CD20 (Rituximab) CD20 Malign B-hücresi 1 3 Kompleman NK CD20 Direkt apoptozis indüksiyonu 2 11 Male D et al, Adv Immunol, 1996

Transplantasyondan önce R-ICE vs R-DHAP (CORAL) Transplantasyondan önce %63 %64 Gisselbrecht C et al, JCO, 2010

KT ve Rituximab’a direnç R-ICE vs R-DHAP (OS, PFS, EFS) %51 %42 %47 3. yılda %31 3. yılda KT’ye direnç a) 3 yıllık OS %47 ve %51 idi ve fark bulunmadı. B) 3 yıllık PFS %31 ve %42 idi, fark bulunmadı. CORAL’a göre daha önceden R kullanılmış olması EFS’yi kötü etkilemekte. Relaps <12 ay KT ve Rituximab’a direnç Relaps >12 ay Gisselbrecht C et al, JCO, 2010

Gisselbrecht C et al, JCO, 2010 R-ICE vs R-DHAP (PFS) %53 3. yılda Gisselbrecht C et al, JCO, 2010

Palanca-Wessels MCA et al, Cancer, 2010 Radioimmunotherapy 131I ve 90Y anti-CD20 Radionüklidin direkt olarak tümör hücresinin yüzeyine naklini sağlar Sitotoksik etki artar “Crossfire effect” gösterir İşaretli olmayan 1mg/kg predoz anti-CD20 ile splenik uptake azaltılır Over time, as the radionuclide decays, the particles released cross several cell diameters, leading to a significant radiation exposure to cells not bound by the antibody. This “crossfi re effect” is thought to lead to a signifi cantly higher penetration within involved lymphoma lesions, particularly in the setting of bulky disease or in poorly perfused regions.1 Palanca-Wessels MCA et al, Cancer, 2010

Relaps NHL’de radiolabeled anti-CD20 antikorlar Cevap yüzdesi “naked” anti-CD20’den daha yüksektir Cevap süresi “naked” anti-CD20’lere ~ benzer Yüksek doz (2-3 kezde 0.8-1.2 mCi/kg):response (5-10 yıl) kür? “Naked” anti-CD20’ye dirençli hastalarda da etkili 16

131I-tositumomab (BexxarTM)/Cy/VP16 vs TBI/Cy/VP16 (OS, PFS) ABD n=52, n=105 relaps NHL OKİT Figure 1. Overall survival of patients with relapsed B-cell lymphomas with 2 treatments. Fifty-two patients were treated with 131I-tositumomab, etoposide, cyclophosphamide, and autologous stem-cell transplantation (ASCT) (thin line), and 105 patients were treated with external-beam total-body irradiation (TBI) (1.5 Gy twice a day for 4 days), etoposide (60 mg/kg), cyclophosphamide (100 mg/kg), and ASCT (thick line). Figure 2. Progression-free survival in patients with relapsed B-cell lymphomas. Fifty-two patients were treated with 131I-tositumomab, etoposide, cyclophosphamide, and ASCT (thin line), and 105 patients were treated with external-beam TBI (1.5 Gy twice a day for 4 days), etoposide (60 mg/kg), cyclophosphamide (100 mg/kg), and ASCT (thick line). Press OW et al, Blood, 2000

Figure 3. Survival analyses according to type of lymphoma Figure 3. Survival analyses according to type of lymphoma. (A) Overall survival in 38 patients with relapsed indolent lymphomas (thin solid line) and 14 patients with relapsed aggressive lymphomas (short dashes) treated with 131I-tositumomab, etoposide, cyclophosphamide, and ASCT and in 44 patients with relapsed indolent lymphomas (thick solid line) and 60 patients with relapsed aggressive lymphomas (long thick dashes) treated with external-beam TBI (1.5 Gy twice a day for 4 days), etoposide (60 mg/kg), cyclophosphamide (100 mg/kg), and ASCT. (B) Progressionfree survival in 38 patients with relapsed indolent lymphomas (thin solid line) and 14 patients with relapsed aggressive lymphomas (short dashes) treated with 131Itositumomab, etoposide, cyclophosphamide, and ASCT and in 44 patients with relapsed indolent lymphomas (thick solid line) and 60 patients with relapsed aggressive lymphomas (long thick dashes) treated with external-beam TBI (1.5 Gy twice a day for 4 days), etoposide (60 mg/kg), cyclophosphamide, (100 mg/kg) and ASCT. Press OW et al, Blood, 2000

Myeloablative 131I-rituximab n=23 relaps/refrakter NHL, %50’si rituximab kullanmamış 9 olgu RIT, 6 olgu RIT+EAM, 8 olgu RIT+BEAM takiben OKİT %64 CR %23 PR OS 101.5 ay PFS 47.5 ay %100 grade IV hematolojik toksisite EAM: etoposide, cytarabine, melphalan Deshayes E et al, Immunotherapy, 2013

90Y-Ibritumomab tiuxetan (Zevalin™) Fare anti-CD20 S NH C NH 90 20

1-2 risk faktörü varlığında 90Y-Ibritumomab Tiuxetan (ZevalinTM)- BEAM vs BEAM takiben OKİT Risk faktörüne göre; * > 55 yaş * 12 ay içinde relaps * tx öncesi + PET Figure 1. (Top) Progression-free survival is shown according to conditioning regimen, standard-dose ibritumomab tiuxetan combined with high-dose BEAM (Z-BEAM) versus BEAM. (Middle) Progression-free survival is shown by the number of poor risk factors (RF) among 1) age 55 years, 2) high-risk disease (relapse within 12 months of diagnosis and/or secondary International Prognostic Index >2), and 3) positive pretransplant positron emission tomography combined with computerized tomography. (Bottom) Progression-free survival is shown according to conditioning regimen among patients with 1 or 2 risk factors. ABD, Avrupa, Asya, Afrika Z-BEAM n=22, BEAM n=21 1-2 risk faktörü varlığında Shimoni A et al, Cancer, 2012

%91 %62 Figure 2. Overall survival is shown according to conditioning regimen: standard-dose ibritumomab tiuxetan combined with high-dose BEAM (Z-BEAM) versus BEAM. 2. yılda Shimoni A et al, Cancer, 2012

90Y-Ibritumomab Tiuxetan (Zevalin®) (OS, PFS, NRM ve relaps) BEAM eligible olmayan kötü-riskli relaps/refrakter 60 NHL R- içeren yüksek doz ardışık KT 90Y-Ibritumomab OKİT %72.9 %62.7 %32.5 5. yılda 5. yılda %1.7 Devizzi L et al, JCO, 2013

Ayala E, Cancer Control, 2012

NHL tedavisinde yeni hedefler 25

Pixantrone (topoisomerase II inhibitor) The National Institute for Health and Care Excellence (NICE), Relaps/refrakter agressif NHL’nin monoterapisinde 50mg/m2 28 günlük siklusun 1, 8 ve 15. günlerinde 6 siklus Diğer antrasiklinlerden daha iyi kardiak profili mevcut FDA approved: Yok

Pixantrone (Flud+Pix+Dex-R) (OS ve TTP) % > 90 Tablo 5: The overall response rate (CR, CRu, and PR) of any duration in the efficacy-evaluable population was 89% (Table 5). Nineteen (70%) patients had a response of CR, CRu, or PR that lasted at least 8 weeks; the median duration of these responses was 23 months, and the longest was >40 Months. Diğer şekil: OS tüm zamanlarda %90’ın üzerinde. Progresyona kadar geçen süre ise slayta bak Srokowski TP et al, Cancer, 2011

Pettengell R et al, Lancet Oncol, 2012 Pixantrone n= 70, relaps/refrakter agressif NHL, Faz III Pixantrone VS vino, oxa, ifosf, etop, mit, veya gem CR veya CRu %20 vs %5-7 Nötropeni %28 vs %13, trombositopeni %16 vs %5 Pettengell R et al, Lancet Oncol, 2012

Bendamustine Mustard grubunun alkilleyici aktivitesi + purin analoğu yapısının antimetabolit aktivitesi Apoptotik yolakların aktivasyonu asıl özelliğidir. Ancak apoptotik yolaklar inhibe olduğunda ve multiresistant hücre dizilerinde dahi etkin bulunmuştur.

Ohmachi K et al, Cancer Sci, 2010 Bendamustine (PFS) n= 69, relaps/refrakter indolent B-NHL ve MCL, Faz II 120mg/m2 1 ve 2. günler, 21 günlük siklus, 5 siklus %90 %73.6 %70.4 1. yılda Ohmachi K et al, Cancer Sci, 2010

Friedberg JW et al, Blood, 2011 Benda-Bort-Ritux n= 31, relaps/refrakter indolent B-NHL ve MCL 28-günlük 6 siklus CR 24(%83) PFS (2-yıl) %47 Yan etki profili: Bulantı %50 Nöropati %47 Konstipasyon %47 Ateş %40 Friedberg JW et al, Blood, 2011

BeEAM (DFS) n= 28, relaps/refrakter NHL 18. ayda %81 18. ayda n= 28, relaps/refrakter NHL Bendamustine, etoposide, cytarabine, melphalan chemosensitive chemoresistant Visani G et al, Blood, 2011

Stopeck AT et al, Leuk Lymphoma, 2009 Bevacizumab (PFS, OS) VEGF’e karşı monoklonal antikor n= 52, refrakter DLCL veya MCL Faz-II çalışması (SWOG), 2 haftada bir 10mg/kg IV %53 6. ayda 6. ayda %16 Stopeck AT et al, Leuk Lymphoma, 2009

Clofarabine (ORR, PFS) 2. jenerasyon deoksiadenosin nükleozid analoğu Fludarabine+Cladribin’in farmakokinetik özelliklerini gösterir DNA sentez inhibisyonu + apoptozis indüksiyonu Düşük nörotoksisite n= 21, relaps/ R-refrakter NHL 36. ayda %16 Nabhan C et al, Cancer, 2011

Baiocchi RA et al, Cancer, 2011 R-BOR (PFS) FL + MCL n=25 relaps/refrakter MCL, FL %24 2. yıl FL MCL Baiocchi RA et al, Cancer, 2011

Lenalidomide (PFS) n=179 relaps/refrakter agressif NHL, Faz II Vode JM et al, BJH, 2013

Hernandez- Ilizaliturri FJ et al, Cancer, 2011 Lenalidomide GCB- NHL’lar çok daha fazla sayıda kromozomal anormallikler gösterirler n=40, relaps-refrakter DLCL; GCB vs non-GCB Hernandez- Ilizaliturri FJ et al, Cancer, 2011

Hernandez- Ilizaliturri FJ et al, Cancer, 2011 Lenalidomide (PFS, OS) Hernandez- Ilizaliturri FJ et al, Cancer, 2011

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