Nivolumab for relapsed or refractory Hodgkin lymphoma: Real-life experience

PubMedID: 28961828Background: Reed-Sternberg cells of classical Hodgkin's lymphoma (cHL) are characterized by genetic alterations at the 9p24.1 locus, leading to over-expression of programmed death-ligand 1 and 2. In a phase 1b study, nivolumab, a PD-1-blocking antibody, produced a high response in patients with relapsed or refractory cHL, with an acceptable safety profile. Patients and methods: We present a retrospective analysis of 82 patients (median age: 30 years; range: 18-75) with relapsed/refractory HL treated with nivolumab in a named patient program from 24 centers throughout Turkey. The median follow-up was 7 months, and the patients had a median of 5 (2-11) previous lines of therapy. Fifty-seven (70%) and 63 (77%) had been treated by stem-cell transplantation and brentuximab vedotin, respectively. Results: Among 75 patients evaluated after 12 weeks of nivolumab treatment, the objective response rate was 64%, with 16 complete responses (CR; 22%); after 16 weeks, it was 60%, with 16 (26%) patients achieving CR. Twenty patients underwent subsequent transplantation. Among 11 patients receiving allogeneic stem-cell transplantation, 5 had CR at the time of transplantation and are currently alive with ongoing response. At the time of analysis, 41 patients remained on nivolumab treatment. Among the patients who discontinued nivolumab, the main reason was disease progression (n = 19). The safety profile was acceptable, with only four patients requiring cessation of nivolumab due to serious adverse events (autoimmune encephalitis, pulmonary adverse event, and two cases of graft-versus-host disease aggravation). The 6-month overall and progression-free survival rates were 91.2% (95% confidence interval: 0.83-0.96) and 77.3% (0.66-0.85), respectively. Ten patients died during the follow-up; one of these was judged to be treatment-related. Conclusions: Nivolumab represents a novel option for patients with cHL refractory to brentuximab vedotin, and may serve as a bridge to transplantation; however, it may be associated with increased toxicity. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved

Nivolumab for relapsed or refractory Hodgkin lymphoma: Real-life experience

Background: Reed-Sternberg cells of classical Hodgkin's lymphoma (cHL) are characterized by genetic alterations at the 9p24.1 locus, leading to over-expression of programmed death-ligand 1 and 2. In a phase 1b study, nivolumab, a PD-1-blocking antibody, produced a high response in patients with relapsed or refractory cHL, with an acceptable safety profile. Patients and methods: We present a retrospective analysis of 82 patients (median age: 30 years; range: 18-75) with relapsed/refractory HL treated with nivolumab in a named patient program from 24 centers throughout Turkey. The median follow-up was 7 months, and the patients had a median of 5 (2-11) previous lines of therapy. Fifty-seven (70%) and 63 (77%) had been treated by stem-cell transplantation and brentuximab vedotin, respectively. Results: Among 75 patients evaluated after 12 weeks of nivolumab treatment, the objective response rate was 64%, with 16 complete responses (CR; 22%); after 16 weeks, it was 60%, with 16 (26%) patients achieving CR. Twenty patients underwent subsequent transplantation. Among 11 patients receiving allogeneic stem-cell transplantation, 5 had CR at the time of transplantation and are currently alive with ongoing response. At the time of analysis, 41 patients remained on nivolumab treatment. Among the patients who discontinued nivolumab, the main reason was disease progression (n = 19). The safety profile was acceptable, with only four patients requiring cessation of nivolumab due to serious adverse events (autoimmune encephalitis, pulmonary adverse event, and two cases of graft-versus-host disease aggravation). The 6-month overall and progression-free survival rates were 91.2% (95% confidence interval: 0.83-0.96) and 77.3% (0.66-0.85), respectively. Ten patients died during the follow-up; one of these was judged to be treatment-related. Conclusions: Nivolumab represents a novel option for patients with cHL refractory to brentuximab vedotin, and may serve as a bridge to transplantation; however, it may be associated with increased toxicity

TÜRK TOPLUMUNDA EN SIK RASTLANILAN MİYOFOSFORİLAZ (PYGM) MUTASYONLARI: MCARDLE HASTALIĞININ GENETİK TANISI İÇİN YENİ NESİL DİZİLEME

Amaç: Miyofosforilaz enzimini kodlayan PYGM genindeki mutasyonlar, enzimde aktivite eksikliğine neden olarak glikojen depo hastalığı tip V (GDHV – McArdle hastalığı) fenotipini ortaya çıkarmaktadır. Dünya genelinde en sık rastlanılan PYGM mutasyonları sırasıyla p.Arg50X ve p.Arg488X nokta mutasyonları olup, proteinde erken sonlanmaya neden olan anlamsız mutasyonlardır. Bu çalışmada ülkemizde genetik tanının konulabilmesi ve bu testlerin tanı akışında kas biyopsisinin önüne geçebilmesi için, Türk McArdle hastalarında PYGM geninde en sık görülen mutasyonların yeni nesil dizileme (YND) teknikleri ile belirlenmesi ve moleküler yöntemler ile bir tanı algoritması oluşturulması amaçlanmaktadır. Gereç ve Yöntem: Çalışma, daha önce kas biyopsisinde enzim histokimya ile miyofosforilaz enzim eksikliği tanısı konmuş 19 aileden oluşan hasta ve aile fertleri ile yürütülmüştür (n=34). Kontrol grubu sağlıklı hastalarla akrabalık ilişkisi bulunmayan ve miyopati klinik bulguları taşımayan kişilerden oluşturulmuştur (n=53). Hastalardan elde edilen DNA Illumina Miseq sisteminde YND ile dizilenmiştir. Dizileme verileri Burrows-Wheeler Aligner ile insan genom sekansına hizalanmış (hg19), BAM dosyaları SAMtool ile okunmuş, tek nükleotid polimorfizmler ve küçük insersiyon-delesyonların tespitinde GATK, fonksiyonel anotasyonların tespitinde SnpEff ve varyant filtreleme için VarSifter kullanılmıştır. Bulgular: Çalışma grubumuzda PYGM’de en çok rastlanılan mutasyon p.Met1Val/c.1A>G (hasta/aile=18/7) nokta mutasyonudur ve daha önce Türk kökenli bir hastada saptanmıştır. Çalışmada tespit edilen diğer mutasyonlar, p.621Phe_622Iledel/c.1864_1865delCTT (6/4), yeni keşfedilen g.4853_4854delTG (4/3), p.Arg488X/c.1462C>T (3/3) ve p.665Lys_666Glnfs/c.1998_1999delA (2/1) olarak sıralanmıştır. Bunların dışında, dünya genelinde hot-spot olan p.Arg50X (1) erken sonlanma mutasyonu sadece tek bir hastada belirlenmiştir. Sonuç: Türk GDHV hastalarında en sık rastlanılan p.Met1Val/c.1A>G mutasyonu, başlangıç kodonunu ortadan kaldırdığından, enzim translasyonunu yok ederek McArdle fenotipinin ortaya çıkmasına neden olmaktadır. Hastalarda, daha az olmakla birlikte, 5 ayrı mutasyon daha belirlenmiştir. Bu çalışmada g.4853_4854delTG mutasyonu 3 farklı ailede saptanan yeni bir mutasyon olup, diğerleri daha önce başka çalışmalarda tespit edilmiştir. YND teknikleri ile, Türkiye’den 19 ailede ortak PYGM mutasyonları belirlenmiş ve moleküler tanı için bir akış şeması oluşturulmuştur

Nivolumab for relapsed or refractory Hodgkin lymphoma: real-life experience.

BACKGROUND: Reed-Sternberg cells of classical Hodgkin's lymphoma (cHL) are characterized by genetic alterations at the 9p24.1 locus, leading to over-expression of programmed death-ligand 1 and 2. In a phase 1b study, nivolumab, a PD-1-blocking antibody, produced a high response in patients with relapsed or refractory cHL, with an acceptable safety profile. PATIENTS AND METHODS: We present a retrospective analysis of 82 patients (median age: 30 years; range: 18-75) with relapsed/refractory HL treated with nivolumab in a named patient program from 24 centers throughout Turkey. The median follow-up was 7 months, and the patients had a median of 5 (2-11) previous lines of therapy. Fifty-seven (70%) and 63 (77%) had been treated by stem-cell transplantation and brentuximab vedotin, respectively. RESULTS: Among 75 patients evaluated after 12 weeks of nivolumab treatment, the objective response rate was 64%, with 16 complete responses (CR; 22%); after 16 weeks, it was 60%, with 16 (26%) patients achieving CR. Twenty patients underwent subsequent transplantation. Among 11 patients receiving allogeneic stem-cell transplantation, 5 had CR at the time of transplantation and are currently alive with ongoing response. At the time of analysis, 41 patients remained on nivolumab treatment. Among the patients who discontinued nivolumab, the main reason was disease progression (n = 19). The safety profile was acceptable, with only four patients requiring cessation of nivolumab due to serious adverse events (autoimmune encephalitis, pulmonary adverse event, and two cases of graft-versus-host disease aggravation). The 6-month overall and progression-free survival rates were 91.2% (95% confidence interval: 0.83-0.96) and 77.3% (0.66-0.85), respectively. Ten patients died during the follow-up; one of these was judged to be treatment-related. CONCLUSIONS: Nivolumab represents a novel option for patients with cHL refractory to brentuximab vedotin, and may serve as a bridge to transplantation; however, it may be associated with increased toxicity