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1. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial

Author

Richardson, Paul G, Oriol, Albert, Beksac, Meral, Liberati, Anna Marina, Galli, Monica, Schjesvold, Fredrik, Lindsay, Jindriska, Weisel, Katja, White, Darrell, Facon, Thierry, San Miguel, Jesus, Sunami, Kazutaka, O'Gorman, Peter, Sonneveld, Pieter, Robak, Pawel, Semochkin, Sergey, Schey, Steve, Yu, Xin, Doerr, Thomas, Bensmaine, Amine, Biyukov, Tsvetan, Peluso, Teresa, Zaki, Mohamed, Anderson, Kenneth, Dimopoulos, Meletios, OPTIMISMM trial investigators, Abildgaard N, Adler H, Altuntas F, Akay OM, Amin B, Anagnostopoulos A, Anderson L, Anttila P, Araujo C, Arce-Lara C, Aydin Y, Basu S, Battini R, Beeker T, Benboubker L, Ben-Yehuda D, Bladé J, Blau IW, Boccia R, Burke L, Byeff P, Cascavilla N, Cavo M, Chantry A, Charles Y, Chaudhry A, Corso A, Coyne M, De Arriba F, Delimpasi S, Desjardins P, Dhakal B, Di Bartolomeo P, Di Raimondo F, Dürig J, Engelhardt M, Escoffre-Barbe M, Esteves G, Flogegard M, Gabrail N, Gamberi B, Garrison M, Gay J, Gisslinger H, Goldschmidt H, Goncalves C, Gressot L, Grosicki S, Hanna W, Hayden P, Henriques Bernardo MM, Hermann R, Holden V, Honkalehto K, Huben M, Huffman J, Hunter H, Hus M, Jagasia M, Jagganath S, Janakiram M, Jaiyesimi I, Jenner M, João C, Johnson P, Jurcyszyn A, Kalayoğlu Beşişik S, Kambhampati S, Kanate A, Karadoğan I, Khojasteh A, Kirkel D, Komarnicki M, Krauth MT, Kuriakose P, Larocca A, Lauri B, Leleu X, Lucio P, Luppi M, Mangiacavalli S, Mariette C, Matsue K, Mellqvist UH, Mendeleeva L, Meshad M, Miller C, Mohrbacher A, Moreau P, Morelli AM, Müldür E, Naassan A, Nahi H, Nair R, O'Dwyer M, Öngören Aydin S, Openshaw T, O'Rourke T, Osswald M, Overton L, Pati A, Pavic M, Pegourie B, Pehlivan M, Pierola AA, Plesner T, Pluta A, Rabin N, Ramasamy K, Rambaldi A, Rodriguez P, Röllig C, Rosenblatt J, Rosenbluth J, Salomo M, Samoylova O, Sastre Moral J, Sati H, Selleri C, Shafeek S, Shinagawa A, Sleckman B, Smith C, Sonmez M, Stone C, Streetly M, Suzuki K, Taetle R, Tafuri A, Takezako N, Teke HÜ, Vapaatalo M, Vassilopoulos G, Verma A, Vidito S, Viterbo L, Vural F, Wang XS, Yağci M, Yee A., Richardson, Paul G, Oriol, Albert, Beksac, Meral, Liberati, Anna Marina, Galli, Monica, Schjesvold, Fredrik, Lindsay, Jindriska, Weisel, Katja, White, Darrell, Facon, Thierry, San Miguel, Jesu, Sunami, Kazutaka, O'Gorman, Peter, Sonneveld, Pieter, Robak, Pawel, Semochkin, Sergey, Schey, Steve, Yu, Xin, Doerr, Thoma, Bensmaine, Amine, Biyukov, Tsvetan, Peluso, Teresa, Zaki, Mohamed, Anderson, Kenneth, Dimopoulos, Meletio, OPTIMISMM trial investigator, Abildgaard N, Adler H, Altuntas F, Akay OM, Amin B, Anagnostopoulos A, Anderson L, Anttila P, Araujo C, Arce-Lara C, Aydin Y, Basu S, Battini R, Beeker T, Benboubker L, Ben-Yehuda D, Bladé J, Blau IW, Boccia R, Burke L, Byeff P, Cascavilla N, Cavo M, Chantry A, Charles Y, Chaudhry A, Corso A, Coyne M, De Arriba F, Delimpasi S, Desjardins P, Dhakal B, Di Bartolomeo P, Di Raimondo F, Dürig J, Engelhardt M, Escoffre-Barbe M, Esteves G, Flogegard M, Gabrail N, Gamberi B, Garrison M, Gay J, Gisslinger H, Goldschmidt H, Goncalves C, Gressot L, Grosicki S, Hanna W, Hayden P, Henriques Bernardo MM, Hermann R, Holden V, Honkalehto K, Huben M, Huffman J, Hunter H, Hus M, Jagasia M, Jagganath S, Janakiram M, Jaiyesimi I, Jenner M, João C, Johnson P, Jurcyszyn A, Kalayoğlu Beşişik S, Kambhampati S, Kanate A, Karadoğan I, Khojasteh A, Kirkel D, Komarnicki M, Krauth MT, Kuriakose P, Larocca A, Lauri B, Leleu X, Lucio P, Luppi M, Mangiacavalli S, Mariette C, Matsue K, Mellqvist UH, Mendeleeva L, Meshad M, Miller C, Mohrbacher A, Moreau P, Morelli AM, Müldür E, Naassan A, Nahi H, Nair R, O'Dwyer M, Öngören Aydin S, Openshaw T, O'Rourke T, Osswald M, Overton L, Pati A, Pavic M, Pegourie B, Pehlivan M, Pierola AA, Plesner T, Pluta A, Rabin N, Ramasamy K, Rambaldi A, Rodriguez P, Röllig C, Rosenblatt J, Rosenbluth J, Salomo M, Samoylova O, Sastre Moral J, Sati H, Selleri C, Shafeek S, Shinagawa A, Sleckman B, Smith C, Sonmez M, Stone C, Streetly M, Suzuki K, Taetle R, Tafuri A, Takezako N, Teke HÜ, Vapaatalo M, Vassilopoulos G, Verma A, Vidito S, Viterbo L, Vural F, Wang XS, Yağci M, Yee A., and Hematology

Subjects
Oncology, Adult, Male, medicine.medical_specialty, Adolescent, Population, Dexamethasone, Bortezomib, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, education, Survival rate, Lenalidomide, Multiple myeloma, Aged, Salvage Therapy, education.field_of_study, business.industry, Pomalidomide, bortezomib, dexamethasone, Middle Aged, Pomalidomide, medicine.disease, Prognosis, Thalidomide, Survival Rate, Regimen, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Female, Neoplasm Recurrence, Local, business, Multiple Myeloma, 030215 immunology, medicine.drug, Follow-Up Studies
Abstract

Background As lenalidomide becomes increasingly established for upfront treatment of multiple myeloma, patients refractory to this drug represent a population with an unmet need. The combination of pomalidomide, bortezomib, and dexamethasone has shown promising results in phase 1/2 trials of patients with relapsed or refractory multiple myeloma. We aimed to assess the efficacy and safety of this triplet regimen in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. Methods We did a randomised, open-label, phase 3 trial at 133 hospitals and research centres in 21 countries. We enrolled patients (aged >= 18 years) with a diagnosis of multiple myeloma and measurable disease, an Eastern Cooperative Oncology Group performance status of 0-2, who received one to three previous regimens, including a lenalidomide-containing regimen for at least two consecutive cycles. We randomly assigned patients (1:1) to bortezomib and dexamethasone with or without pomalidomide using a permutated blocked design in blocks of four, stratified according to age, number of previous regimens, and concentration of beta(2) microglobulin at screening. Bortezomib (1.3 mg/m(2)) was administered intravenously until protocol amendment 1 then either intravenously or subcutaneously on days 1,4, 8, and 11 for the first eight cycles and subsequently on days 1 and 8. Dexamethasone (20 mg [10 mg if age >75 years]) was administered orally on the same days as bortezomib and the day after. Patients allocated pomalidomide received 4 mg orally on days 1-14. Treatment cycles were every 21 days. The primary endpoint was progression-free survival in the intention-to-treat population, as assessed by an independent review committee. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered at ClinicalTrials.gov, number NCT01734928; patients are no longer being enrolled. Findings Between Jan 7, 2013, and May 15,2017,559 patients were enrolled. 281 patients were assigned pomalidomide, bortezomib, and dexamethasone and 278 were allocated bortezomib and dexamethasone. Median follow-up was 15.9 months (IQR 9.9-21.7). Pomalidomide, bortezomib, and dexamethasone significantly improved progression-free survival compared with bortezomib and dexamethasone (median 11.20 months [95% CI 9.66-13-73] vs 7.10 months [5.88-8-48]; hazard ratio 0.61, 95% CI 0.49-0-77; p

Published
2019

2. Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial

Author

Mateos, Maria-Victoria, Blacklock, Hilary, Schjesvold, Fredrik, Oriol, Albert, Simpson, David, George, Anupkumar, Goldschmidt, Hartmut, Larocca, Alessandra, Chanan-Khan, Asher, Sherbenou, Daniel, Avivi, Irit, Benyamini, Noam, Iida, Shinsuke, Matsumoto, Morio, Suzuki, Kenshi, Ribrag, Vincent, Usmani, Saad Z, Jagannath, Sundar, Ocio, Enrique M, Rodriguez-Otero, Paula, San Miguel, Jesus, Kher, Uma, Farooqui, Mohammed, Liao, Jason, Marinello, Patricia, Lonial, Sagar, KEYNOTE-183 Investigators, Nicol A, Grigoriadis G, Catalano J, LeBlanc R, Elemary M, Bahlis N, Facon T, Karlin L, Ribrag V, Attal M, Goldschmidt H, Engelhardt M, Weisel K, Mackensen A, Nagler A, Ben Yehuda D, Avivi I, Benyamini N, Magen-Nativ H, Palumbo A, Cavo M, Tobinai K, Iida S, Chou T, Suzuki K, Kosugi H, Taniwaki M, Sunami K, Matsumoto M, Ando K, Ganly P, Blacklock H, Simpson D, George A, Schjesvold F, Gjertsen B, Lahuerta J, Blade J, Oriol Rocafiguera A, Mateos M, Rodriguez-Otero P, Larson S, Atanackovic D, Devarakonda S, Bitran J, Zonder J, Morganstein N, Hay M, Chanan-Khan A, Saylors G, Kio E, Oliff I, Kirkel D, Shtivelband M, Yuen C, Yee A, Shah J, Htut M, Raza S, Chhabra S, Stiff P, Hari P, Bank B, Malek E, Gasparetto C, Faroun Y, Sherbenou D, Kreisle W, Singhal S, Rosenblatt J, Usmani S, Lee W, Safah H, Lutzky J, Suh J, Pan D, Baron A, Manges R, Steis R, Oliveira M, Moreb J, Callander N, Anz B, Raptis A, Stampleman L, Melear J, Boyd T, Garbo L, Klein L, Shao S, Lyons R, McIntyre K, Tarantolo S, Yasenchak C, Yimer H., Mateos, Maria-Victoria, Blacklock, Hilary, Schjesvold, Fredrik, Oriol, Albert, Simpson, David, George, Anupkumar, Goldschmidt, Hartmut, Larocca, Alessandra, Chanan-Khan, Asher, Sherbenou, Daniel, Avivi, Irit, Benyamini, Noam, Iida, Shinsuke, Matsumoto, Morio, Suzuki, Kenshi, Ribrag, Vincent, Usmani, Saad Z, Jagannath, Sundar, Ocio, Enrique M, Rodriguez-Otero, Paula, San Miguel, Jesu, Kher, Uma, Farooqui, Mohammed, Liao, Jason, Marinello, Patricia, Lonial, Sagar, KEYNOTE-183 Investigator, and Nicol A, Grigoriadis G, Catalano J, LeBlanc R, Elemary M, Bahlis N, Facon T, Karlin L, Ribrag V, Attal M, Goldschmidt H, Engelhardt M, Weisel K, Mackensen A, Nagler A, Ben Yehuda D, Avivi I, Benyamini N, Magen-Nativ H, Palumbo A, Cavo M, Tobinai K, Iida S, Chou T, Suzuki K, Kosugi H, Taniwaki M, Sunami K, Matsumoto M, Ando K, Ganly P, Blacklock H, Simpson D, George A, Schjesvold F, Gjertsen B, Lahuerta J, Blade J, Oriol Rocafiguera A, Mateos M, Rodriguez-Otero P, Larson S, Atanackovic D, Devarakonda S, Bitran J, Zonder J, Morganstein N, Hay M, Chanan-Khan A, Saylors G, Kio E, Oliff I, Kirkel D, Shtivelband M, Yuen C, Yee A, Shah J, Htut M, Raza S, Chhabra S, Stiff P, Hari P, Bank B, Malek E, Gasparetto C, Faroun Y, Sherbenou D, Kreisle W, Singhal S, Rosenblatt J, Usmani S, Lee W, Safah H, Lutzky J, Suh J, Pan D, Baron A, Manges R, Steis R, Oliveira M, Moreb J, Callander N, Anz B, Raptis A, Stampleman L, Melear J, Boyd T, Garbo L, Klein L, Shao S, Lyons R, McIntyre K, Tarantolo S, Yasenchak C, Yimer H.

Subjects
Male, medicine.medical_specialty, Pembrolizumab, Antibodies, Monoclonal, Humanized, Dexamethasone, Drug Administration Schedule, 03 medical and health sciences, Pembrolizumab, pomalidomide, dexamethasone, KEYNOTE-183, 0302 clinical medicine, Recurrence, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Progression-free survival, Survival rate, Multiple myeloma, Aged, Proportional Hazards Models, Lenalidomide, Aged, 80 and over, Performance status, business.industry, Hematology, medicine.disease, Pomalidomide, Interim analysis, Progression-Free Survival, Thalidomide, Survival Rate, Myocarditis, Editorial Commentary, Treatment Outcome, Stevens-Johnson Syndrome, 030220 oncology & carcinogenesis, Female, Multiple Myeloma, business, 030215 immunology, medicine.drug
Abstract

Summary Background Pomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whom bortezomib and lenalidomide treatment has failed. KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma. Here, we present the findings of an unplanned, ad-hoc interim analysis at the request of the US Food and Drug Administration (FDA). Methods KEYNOTE-183 was a randomised, open-label, phase 3 trial done at 97 medical centres across 11 countries (Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA). Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy (excluding pomalidomide) and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system. Patients received oral pomalidomide 4 mg daily on days 1–21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov , number NCT02576977 , and it is closed for accrual. Findings Between Jan 18, 2016, and June 7, 2017, 249 patients were randomly assigned to either the pembrolizumab plus pomalidomide and dexamethasone group (n=125) or the pomalidomide and dexamethasone group (n=124). On July 3, 2017, the FDA established that risks associated with the triple combination outweighed benefits and halted the study. Median follow-up was 8·1 months (IQR 4·5–10·9). Median progression-free survival was 5·6 months (95% CI 3·7–7·5) in the pembrolizumab plus pomalidomide and dexamethasone group versus 8·4 months (5·9–not reached) in the pomalidomide and dexamethasone group; progression-free survival estimates at 6 months were 48% (95% CI 37–58) versus 60% (49–69) at 6 months (hazard ratio [HR] 1·53; 95% CI 1·05–2·22; p=0·98). Median overall survival was not reached (95% CI 12·9–not reached) versus 15·2 months (12·7–not reached; HR 1·61; 95% CI 0·91–2·85; p=0·95); overall survival estimates at 6 months were 82% (95% CI 74–88) versus 90% (82–95). Serious adverse events occurred in 75 (63%) of 120 patients in the pembrolizumab plus pomalidomide and dexamethasone group versus 56 (46%) of 121 patients in the pomalidomide and dexamethasone group. Four (3%) treatment-related deaths occurred in the pembrolizumab plus pomalidomide and dexamethasone group (one each of unknown cause, neutropenic sepsis, myocarditis, and Stevens–Johnson syndrome); myocarditis and Stevens-Johnson syndrome were considered related to pembrolizumab. No treatment-related deaths were reported in the pomalidomide and dexamethasone group. Interpretation The results from this unplanned, FDA-requested, interim analysis showed that the benefit–risk profile of pembrolizumab plus pomalidomide and dexamethasone is unfavourable for patients with relapsed or refractory multiple myeloma. Funding Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA).

Published
2019

3. Limited clinical relevance of imaging techniques in the follow-up of patients with advanced chronic lymphocytic leukemia: results of a meta-analysis

Author

Eichhorst, Barbara F, Fischer, Kirsten, Fink, Anna Maria, Elter, Thomas, Wendtner, Clemens M, Goede, Valentin, Bergmann, Manuela, Stilgenbauer, Stephan, Hopfinger, Georg, Ritgen, Matthias, Bahlo, Jasmin, Busch, Raymonde, Hallek, Michael, Oduncu, F, Dreyling, M, Forstpointner, R, Schneller, F, Bogner, C, Peschel, C, Ringshausen, I, Götze, K, Goebeler, Me, Rückle, Lanz, Ritgen, M, Schawitzke, A, Heydrich, B, Kern, K, Böttcher, S, Irmer, S, Strack, U, Borries, V, Klima, Km, Scholz, C, Herold, M, Härtwig, K, Dürig, J, Dührsen, U, Müller Beissenhirtz, H, Noppeney, R, Schüttrumpf, S, Hohloch, K, Binder, C, Hasenkamp, J, Trümper, L, Bäsecke, J, Rieger, M, Witzens Harig, M, Friedrichs, B, Rieger, K, Uharek, L, Kubuschok, B, Murawski, N, Held, G, Zwick, C, Pfreundschuh, M, Fingerle Rowson, G, Reiser, M, Elter, T, Eichhorst, B, Pallasch, C, Hallek, M, Borchmann, P, Hacker, U, Schinkel, S, Wieker, K, Sökler, M, Wolf, Hh, Eucker, J, Staib, P, Schlegel, F, Kropff, M, Kahl, C, Hess, G, Beck, J, Wölfel, T, Bokemeyer, C, Schilling, G, Dierlamm, J, Schüler, F, Busemann, C, Dölken, G, Trendelenburg, Tk, Bühler, A, Stilgenbauer, S, Viardot, A, Greiner, J, Zenz, T, Gaidzik, V, Langer, C, Döhner, H, Werner, I, Dienst, A, Habersang, K, Härtel, N, Leitner, A, Kehrer, G, Middeke, H, Heinisch, K, Adorf, D, Ismer, B, Hering Schubert, C, Jäckle, J, Aulmann, C, Söllner, S, Majunke, P, Fuss, H, Käfer, G, Potenberg, J, Dietrich, G, Hartung, E, Pronath, A, Riedhammer, Fj, Zehrfeld, T, Prümmer, O, Gatter, J, Meier, A, Wattad, M, Heit, W, Sauer, I, Hilgers, K, Geissler, M, Bauer, J, Stein, W, Voigtmann, R, Natt, F, Nickelsen, M, Zeis, M, Schmitz, N, Lange, E, Stoltefuss, A, Schubert, J, Dürk, Ha, Kloke, O, Fauser, A, Roemer, E, Kraut, L, Musch, E, Kohl, S, Link, H, Kirsch, Jf, Schatz, M, Mezger, J, Kempf, B, Heil, G, Derigs, Hg, Roll, C, Kettner, E, Dübbers, Hw, Lutz, L, Hentrich, M, Hoffmann, U, Ibe, M, Falge, C, Schäfer Eckart, K, Rothmann, F, Raghavachar, A, Beckmann, K, Behringer, D, Stauder, H, Hempfling, C, Matzdorff, A, Hähling, D, Kaesberger, Kj, Mück, R, Waladkhani, Ar, Clemens, M, Kraft, J, Ehlert, T, N. N., Schloen, A, Sandritter, B, Scholz, Diekmann, C, Pflüger, Kh, Hausner, G, Fetscher, S, Aulitzky, W, Brugger, W, Frickhofen, N, Fuhr, Lange, C, Lambertz, H, Schulz, L, Schmier, M, Bentz, M, Tauchmann, Gm, Schmidt, M, Meiler, J, Sandmann, M, Kürschner, D, Maier Bay, B, Lindemann, W, Diers, J, Riemeier Sievers, C, Daun, M, Mergenthaler, Hg, Hiller, S, Schirmer, V, Kirchner, H, Langer, W, Günther, B, Gassmann, W, Franke, K, Burghardt, F, Abele, U, Celikel Becker, D, von Weikersthal LF, Brög, G, Hauch, U, Heinrich, B, Brudler, O, Häcker, B, Eckart, Mj, Bolouri, H, Göttler, B, Kindler, M, Zuchold, K, Strohbach, F, Plingen, Ml, Seibt Jung, H, Kirsch, A, Herrenberger, J, Doering, G, von Grünhagen, U, Franke, H, Weniger, J, Kerzel, W, Schmalfeld, M, Rohrberg, R, Hurtz, Hj, Gehbauer, G, Hahnfeld, S, Vehling Kaiser, U, Abenhardt, W, Bosse, D, Böning, L, Schmidt, B, Schick, Hd, Jacobs, G, Stauch, M, Hoffmann, R, Müller, S, Hahn, M, Freier, W, Dietzfelbinger, H, Rassmann, I, Söling, U, Siehl, S, Rudolph, R, Weinert, R, Sauer, A, Meyer, B, Eschenburg, H, Schadeck Gressel, C, Grabenhorst, U, Perker, M, Otremba, B, Reschke, D, Hinrichs, Hf, Zirpel, I, Höring, E, Respondek, M, Köppler, H, Heymanns, J, Weide, R, Hünermund, K, Thiel, C, Reiber, T, Spohn, C, Springer, G, Fiechtner, H, Hübner, A, Kurschel, E, Weiss, J, Schlag, R, Schäfer, E, Hartwich, G, Schmitz, S, Steinmetz, T, Kim, Ts, Lerchenmüller, C, Wehmeyer, J, Laubenstein, Hp, Rendenbach, B, Lebahn, H, Kröning, H, Uhle, R, Balló, H, Gaede, B, Zumbrink, S, Eckert, R, Kamp, T, Reimann, B, Burkhard, O, Mittermüller, J, Hansen, R, Hitz, H, Schliesser, G, Schmitt, Hr, Forstbauer, H, Grundeis, M, Schulze, M, Baldus, M, Lakner, V, Haen, M, Müller, C, Dörfel, S, Göhler, T, Welslau, M, Achtzehn, V, Culmann, H, Gerhardt, S, Ulshöfer, T, Koschuth, A, Schmidt, P, Müller, L, Schneider, M, Koniczek, K, Porowski, P, Glados, M, Knoblich, J, Ben Yehuda, D, Jäger, U, Gaiger, A, Schwarzmeier, J, Nösslinger, T, Smith, M, Patton, N, Gibbons, S, Bouabdallah, R, Gandhi, M, Marlton, P, Mills, T, Angelucci, E, Sorano, Gg, Casula, P, Berneman, Z, Kohser, P, Hudcova Burgetova, A, Machová, R, Papajik, T, Kubová, Z, Fineman, R, Mayer, J, Doubek, M, Brychtova, Y, Ciceri, F, Caligaris Cappio, F, Crocchiolo, R, Dauriac, C, Bernard, M, Escoffre Barbe, M, Lamy, T, Zikesova, E, Karban, J, Salkova, J, Trnený, M, Pytlik, R, Tiley, C, Forsyth, C, Vokurka, S, Koza, V, Van Hoof, A, Selleslag, D, Sebban, C, Baker, B, Belada, D, Jebavy, L, Smolej, L, Pavel, Z, Di Ianni, M, Castaigne, S, Del Poeta, G, Amadori, S, Catalano, J, Ganju, V, Hertzberg, M, Laurenti, L, Dalseg, Am, Bron, D, Morton, J, Durrant, S, Casado, Lf, Theunissen, K, Atias, D, Berkhan, L, Seymour, J, Wolf, M, Bosly, A, Osma Cordoba MM, Portois, C, Jaubert, J, Ferrant, A, Lambert, C, Maerevoet, E, Van den Neste, E, Gadeberg, O, Carney, B, Cannell, P, Eghbali, H, Legouffe, E, Bordessoule, D, Chaury, M, Moreau, S, Pierri, I, Gobbi, M, Berrebi, A, Lishner, M, Yerushazim, R, Yermiaku, T, Kosolov, V, Ambrosetti, Achille, Andreoli, Al, Huguet, F, Laurent, G, Orsucci, L, Forconi, F, Musuraca, G, Zinzani, Pl, Loscertales, J, Mcquillan, A, Cordingley, F, Leahy, M, Cazin, B, Taylor, Mulligan, S, Herbrecht, Cull, G, Seldon, M, Rowlings, P, Ludwig, H, Zojer, N, Solal Céligny, P, Pomponi, F, Savdkova, L, Kozák, T, Christiansen, I, Pérez, I, Campbell, P, Canales Albendea, M, De Paz, R, Arthur, C, Gisselbrecht, C., Eichhorst B.F., Fischer K., Fink A.M., Elter T., Wendtner C.M., Goede V., Bergmann M., Stilgenbauer S., Hopfinger G., Ritgen M., Bahlo J., Busch R., Hallek M., and Zinzani P.L.

Subjects
Male, medicine.medical_specialty, Cyclophosphamide, Chronic lymphocytic leukemia, Immunology, Medizin, Antineoplastic Combined Chemotherapy Protocols, Blood Cell Count, Disease Progression, Disease-Free Survival, Female, Follow-Up Studies, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Middle Aged, Prognosis, Recurrence, Remission Induction, Tomography, X-Ray Computed, Physical examination, Biochemistry, Chemoimmunotherapy, medicine, Chronic, Tomography, Leukemia, medicine.diagnostic_test, business.industry, B-Cell, Cancer, Cell Biology, Hematology, medicine.disease, Lymphocytic, imaging techniques, X-Ray Computed, Fludarabine, Surgery, chronic lymphocytic leukemia, Radiology, business, Progressive disease, medicine.drug
Abstract

The clinical value of imaging is well established for the follow-up of many lymphoid malignancies but not for chronic lymphocytic leukemia (CLL). A meta-analysis was performed with the dataset of 3 German CLL Study Group phase 3 trials (CLL4, CLL5, and CLL8) that included 1372 patients receiving first-line therapy for CLL. Response as well as progression during follow-up was reassessed according to the National Cancer Institute Working Group1996 criteria. A total of 481 events were counted as progressive disease during treatment or follow-up. Of these, 372 progressions (77%) were detected by clinical symptoms or blood counts. Computed tomography (CT) scans or ultrasound were relevant in 44 and 29 cases (9% and 6%), respectively. The decision for relapse treatment was determined by CT scan or ultrasound results in only 2 of 176 patients (1%). CT scan results had an impact on the prognosis of patients in complete remission only after the administration of conventional chemotherapy but not after chemoimmunotherapy. In conclusion, physical examination and blood count remain the methods of choice for staging and clinical follow-up of patients with CLL as recommended by the International Workshop on Chronic Lymphocytic Leukemia 2008 guidelines. These trials are registered at http://www.isrctn.org as ISRCTN 75653261 and ISRCTN 36294212 and at http://www.clinicaltrials.gov as NCT00281918.

Published
2011

4. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma

Author

Stewart, Ak, Rajkumar, Sv, Dimopoulos, Ma, Masszi, T, Špička, I, Oriol, A, Hájek, R, Rosiñol, L, Siegel, Ds, Mihaylov, Gg, Goranova Marinova, V, Rajnics, P, Suvorov, A, Niesvizky, R, Jakubowiak, Aj, San Miguel JF, Ludwig, H, Wang, M, Maisnar, V, Minarik, J, Bensinger, Wi, Mateos, Mv, Ben Yehuda, D, Kukreti, V, Zojwalla, N, Tonda, Me, Yang, X, Xing, B, Moreau, P, Palumbo, A, Petrini, Mario, Aspire, Investigators, Laboratory of Molecullar and Cellular Therapy, and Clinical sciences

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Kaplan-Meier Estimate, Dexamethasone, Ixazomib, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Female, Humans, Intention to Treat Analysis, Middle Aged, Multiple Myeloma, Oligopeptides, Recurrence, Thalidomide, Medicine (all), chemistry.chemical_compound, Internal medicine, 80 and over, medicine, Elotuzumab, Multiple myeloma, Lenalidomide, business.industry, General Medicine, Pomalidomide, medicine.disease, Carfilzomib, Surgery, chemistry, business, medicine.drug
Abstract

BACKGROUND: Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma. The combination of the proteasome inhibitor carfilzomib with lenalidomide and dexamethasone has shown efficacy in a phase 1 and 2 study in relapsed multiple myeloma. METHODS: We randomly assigned 792 patients with relapsed multiple myeloma to carfilzomib with lenalidomide and dexamethasone (carfilzomib group) or lenalidomide and dexamethasone alone (control group). The primary end point was progression-free survival. RESULTS: Progression-free survival was significantly improved with carfilzomib (median, 26.3 months, vs. 17.6 months in the control group; hazard ratio for progression or death, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P=0.0001). The median overall survival was not reached in either group at the interim analysis. The Kaplan-Meier 24-month overall survival rates were 73.3% and 65.0% in the carfilzomib and control groups, respectively (hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P=0.04). The rates of overall response (partial response or better) were 87.1% and 66.7% in the carfilzomib and control groups, respectively (P

Published
2015

5. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib:A multicenter international myeloma working group study

Author

Kumar S. K., Lee J. H., Lahuerta J. J., Morgan G., Richardson P. G., Crowley J., Haessler J., Feather J., Hoering A., Moreau P., LeLeu X., Hulin C., Klein S. K., Sonneveld P., Siegel D., Bladé J., Goldschmidt H., Jagannath S., Miguel J. S., Orlowski R., Palumbo A., Sezer O., Rajkumar S. V., Durie B. G. International Myeloma Working Group Abildgaard N, Abonour R, Alexanian R, Alsina M, Anderson KC, Attal M, Avet Loiseau H, Badros A, Baris D, Barlogie B, Bataille R, Beksaç M, Belch A, Ben Yehuda D, Bensinger B, Bergsagel PL, Bird J, Bladé J, Boccadoro M, Chanan Khan A, Chen WM, Child T, Chim J, Chng WJ, Comenzo R, Crowley J, Dalton W, Davies F, de Souza C, Delforge M, Dimopoulos M, Dispenzieri A, Drach J, Drake M, Durie BG, Einsele H, Facon T, Fantl D, Fermand JP, Fonseca R, Gahrton G, García Sanz R, Gasparetto C, Gertz M, Gibson J, Giralt S, Goldschmidt H, Greipp P, Hajek R, Hardan I, Hari P, Harousseau JL, Hata H, Hattori Y, Heffner T, Ho J, Hungria V, Ida S, Jacobs P, Jagannath S, Johnsen HE, Jian H, Joshua D, Jurczyszyn A, Kawano M, Kröger N, Kumar S, Kyle RA, Lacy M, Lahuerta JJ, Landgren O, Laubach J, Lee JH, LeLeu X, Lentzsch S, Lokhorst H, Lonial S, Ludwig H, Maiolino A, Mateos M, Mehta J, Mellqvist UH, Merlini G, Mikhael J, Morales AR, Moreau P, Morgan G, Nahi H, Munshi N, Niesvizky R, Nouel A, Novis Y, Orlowski R, Palumbo A, Pavlovsky S, Pilarski L, Powles R, Raje N, Rajkumar SV, Reece D, Reiman T, Richardson PG, Roodman D, Rosiñol L, San Miguel J, Sezer O, Shah JJ, Shaughnessy J, Shimizu K, Shustik C, Siegel D, Singhal S, Sonneveld P, Spencer A, Stadtmauer E, Stewart K, Terpos E, Tosi P, Tricot G, Turesson I, Van Camp B, Van Ness B, Van Riet I, Vande Broek I, Vanderkerken K, Vescio R, Vesole D, Waage A, Wang M, Weber D, Westin J, Wheatley K, Zonder J., CAVO, MICHELE, Kumar S.K., Lee J.H., Lahuerta J.J., Morgan G., Richardson P.G., Crowley J., Haessler J., Feather J., Hoering A., Moreau P., LeLeu X., Hulin C., Klein S.K., Sonneveld P., Siegel D., Bladé J., Goldschmidt H., Jagannath S., Miguel J.S., Orlowski R., Palumbo A., Sezer O., Rajkumar S.V., Durie B.G. International Myeloma Working Group Abildgaard N, Abonour R, Alexanian R, Alsina M, Anderson KC, Attal M, Avet-Loiseau H, Badros A, Baris D, Barlogie B, Bataille R, Beksaç M, Belch A, Ben-Yehuda D, Bensinger B, Bergsagel PL, Bird J, Bladé J, Boccadoro M, Cavo M, Chanan-Khan A, Chen WM, Child T, Chim J, Chng WJ, Comenzo R, Crowley J, Dalton W, Davies F, de Souza C, Delforge M, Dimopoulos M, Dispenzieri A, Drach J, Drake M, Durie BG, Einsele H, Facon T, Fantl D, Fermand JP, Fonseca R, Gahrton G, García-Sanz R, Gasparetto C, Gertz M, Gibson J, Giralt S, Goldschmidt H, Greipp P, Hajek R, Hardan I, Hari P, Harousseau JL, Hata H, Hattori Y, Heffner T, Ho J, Hungria V, Ida S, Jacobs P, Jagannath S, Johnsen HE, Jian H, Joshua D, Jurczyszyn A, Kawano M, Kröger N, Kumar S, Kyle RA, Lacy M, Lahuerta JJ, Landgren O, Laubach J, Lee JH, LeLeu X, Lentzsch S, Lokhorst H, Lonial S, Ludwig H, Maiolino A, Mateos M, Mehta J, Mellqvist UH, Merlini G, Mikhael J, Morales AR, Moreau P, Morgan G, Nahi H, Munshi N, Niesvizky R, Nouel A, Novis Y, Orlowski R, Palumbo A, Pavlovsky S, Pilarski L, Powles R, Raje N, Rajkumar SV, Reece D, Reiman T, Richardson PG, Roodman D, Rosiñol L, San Miguel J, Sezer O, Shah JJ, Shaughnessy J, Shimizu K, Shustik C, Siegel D, Singhal S, Sonneveld P, Spencer A, Stadtmauer E, Stewart K, Terpos E, Tosi P, Tricot G, Turesson I, Van Camp B, Van Ness B, Van Riet I, Vande Broek I, Vanderkerken K, Vescio R, Vesole D, Waage A, Wang M, Weber D, Westin J, Wheatley K, Zonder J., and Hematology

Subjects
Adult, Male, Oncology, Cancer Research, medicine.medical_specialty, NATURAL HISTORY, Antineoplastic Agents, Context (language use), RELAPSE, Article, Recurrence, Internal medicine, medicine, Humans, Immunologic Factors, Elotuzumab, Survival analysis, Multiple myeloma, Aged, Aged, 80 and over, Isatuximab, Bortezomib, business.industry, Hematology, Middle Aged, Pomalidomide, medicine.disease, Survival Analysis, Surgery, Regimen, SURVIVAL, Disease Progression, Female, Multiple Myeloma, business, medicine.drug
Abstract

Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive, an IMiD (immunomodulatory drug), had measurable disease, and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T-0). The median age at diagnosis was 58 years, and time from diagnosis to T-0 was 3.3 years. Following T-0, 213 (74%) patients had a treatment recorded with one or more regimens (median = 1; range 0-8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T0 in 94 patients (44%) including >= partial response in 69 (32%). The median overall survival and event-free survival from T-0 were 9 and 5 months, respectively. This study confirms the poor outcome, once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs. Leukemia (2012) 26, 149-157; doi:10.1038/leu.2011.196; published online 29 July 2011

Published
2012

6. Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial

Author

Coiffier, B, Osmanov, E, Hong, X, Scheliga, A, Mayer, J, Offner, F, Rule, S, Teixeira, A, Walewski, J, de Vos, S, Crump, M, Shpilberg, O, Esseltine, D, Zhu, E, Enny, C, Theocharous, P, van de Velde, H, Elsayed, Y, Zinzani, P, Abdulkadyrov, K, Afanasiev, B, Aguayo Gonzalez, A, Andre, M, Belada, D, Ben Yehuda, D, Bezares, R, Biakhov, M, Bolam, S, Borbenyi, Z, Bron, D, Buckstein, R, Bumbea, H, Caballero Barrigon, M, Campos, L, Cantonetti, M, Capra Zanella, M, Christiansen, N, Cohen, G, Colita, N, Cosgriff, T, Culligan, D, Del Giglio, A, Dichmann, R, Dietzfelbinger, H, Digumarti, R, Dmoszynska, A, Domnikova, N, Dubinsky, P, Dunaev, Y, Easow, J, Eberwine, S, Economopoulos, T, Egyed, M, Ellerton, J, Eom, H, Farmer, L, Fenske, T, Fields, P, Fillet, G, Frank, R, Gaisarova, G, Garicochea, B, Gasztonyi, Z, Gavish, I, Gheorghita, E, Gladkov, O, Goldberg, V, Golenkov, A, Gomez Almaguer, D, Gonzalez Barca, E, Guan, Z, Gupta, S, Hellmann, A, Hermann, R, Honkanen, T, Hu, E, Huang, X, Hudecek, J, Illes, A, Intragumtornchai, T, Jedrzejczak, W, Jones, L, Jootar, S, Kahanic, S, Karamanesht, E, Ke, X, Khuageva, N, Kim, W, Kimby, E, Komisarenko, V, Kouroukis, T, Kuliczkowski, K, Kuzina, L, Kyselyova, M, Labanca, V, Lange, A, Le Gouill, S, Leahy, M, Liberati, A, Linden, O, Liu, T, Lubennikov, V, Lundin, J, Lysa, T, Lysenko, I, Lytvyn, I, Makhson, A, Manikhas, G, Masliak, Z, Mcintyre, R, Medvedeva, N, Mena, R, Merkulov, V, Mesters, R, Milpied, N, Min, Y, Moezi, M, Mohrbacher, A, Mollee, P, Morgan, D, Morschhauser, F, Mysanikov, A, Nagler, A, Nair, S, Naparstek, E, Nawarawong, W, Noga, S, Oliveira, I, Okada, C, Oriol Rocafiguera, A, Page, R, Papajik, T, Pasquini, R, Patel, M, Patel, R, Paton, E, Pavlov, V, Pospelova, T, Prasad, S, Pylypenko, H, Raposo, J, Rekhtman, G, Rivas, S, Robak, T, Saba, S, Salles, G, Saltzman, M, Samoilova, O, Samuels, B, Sanani, S, Sebban, C, Silva da Gomes, M, Shen, Z, Shi, Y, Shtalrid, M, Siritanaratkul, N, Skotnicki, A, Solal Celigny, P, Soubeyran, P, Spencer, A, Stevens, D, Suh, C, Sulek, K, Suvorov, A, Szer, J, Theunissen, K, To Bik, L, Tothova, E, Trneny, M, Van De Velde, A, Van Hoof, A, Van Steenweghen, S, Vanhatalo, S, Varma, S, Vidyasagar, M, Vilchevskaya, K, Vitolo, U, Wang, H, Warzocha, K, Wild, A, Zachee, P, Zanichelli, M, Zhang, W, Zoppegno, L, Zoumbos, N, Coiffier B., Osmanov E.A., Hong X., Scheliga A., Mayer J., Offner F., Rule S., Teixeira A., Walewski J., de Vos S., Crump M., Shpilberg O., Esseltine D.L., Zhu E., Enny C., Theocharous P., van de Velde H., Elsayed Y.A., Zinzani P.L., and LYM-3001 study investigators

Subjects
Oncology, Male, Lymphoma, Settore MED/06 - Oncologia Medica, Follicular lymphoma, Bortezomib, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, Maintenance therapy, Prednisone, immune system diseases, Recurrence, hemic and lymphatic diseases, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, 80 and over, Lymphoma, Follicular, Multiple myeloma, Infusion Pumps, Aged, 80 and over, Middle Aged, Boronic Acids, 3. Good health, 030220 oncology & carcinogenesis, Pyrazines, Rituximab, Female, medicine.drug, Murine-Derived, Adult, medicine.medical_specialty, rituximab-naive, Antineoplastic Agents, Antibodies, Disease-Free Survival, 03 medical and health sciences, Young Adult, follicular lymphoma, Internal medicine, Neoplasm Staging, Humans, Aged, medicine, business.industry, Follicular, medicine.disease, Clinical trial, rituximab-sensitive, Immunology, business, Settore MED/15 - Malattie del Sangue, 030215 immunology
Abstract

BACKGROUND: Bortezomib and rituximab have shown additive activity in preclinical models of lymphoma, and have been shown to be active and generally well tolerated in a randomised phase 2 study in patients with follicular and marginal zone lymphoma. We compared the efficacy and safety of rituximab alone or combined with bortezomib in patients with relapsed or refractory follicular lymphoma in a phase 3 setting. METHODS: In this multicentre phase 3 trial, rituximab-naive or rituximab-sensitive patients aged 18 years or older with relapsed grade 1 or 2 follicular lymphoma were randomly assigned (1:1) to receive five 35-day cycles consisting of intravenous infusions of rituximab 375 mg/m(2) on days 1, 8, 15, and 22 of cycle 1, and on day 1 of cycles 2-5, either alone or with bortezomib 1·6 mg/m(2), administered by intravenous injection on days 1, 8, 15, and 22 of all cycles. Randomisation was stratified by FLIPI score, previous use of rituximab, time since last therapy, and region. Treatment assignment was based on a computer-generated randomisation schedule prepared by the sponsor. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00312845. FINDINGS: Between April 10, 2006, and Aug 12, 2008, 676 patients were randomised to receive rituximab (n=340) or bortezomib plus rituximab (n=336). After a median follow-up of 33·9 months (IQR 26·4-39·7), median progression-free survival was 11·0 months (95% CI 9·1-12·0) in the rituximab group and 12·8 months (11·5-15·0) in the bortezomib plus rituximab group (hazard ratio 0·82, 95% CI 0·68-0·99; p=0·039). The magnitude of clinical benefit was not as large as the anticipated prespecified improvement of 33% in progression-free survival. Patients in both groups received a median of five treatment cycles (range 1-5); 245 of 339 (72%) and 237 of 334 (71%) patients in the rituximab and bortezomib plus rituximab groups, respectively, completed five cycles. Of patients who did not complete five cycles, most discontinued early because of disease progression (77 [23%] patients in the rituximab group, and 56 [17%] patients in the bortezomib plus rituximab group). Rates of adverse events of grade 3 or higher (70 [21%] of 339 rituximab-treated patients vs 152 [46%] of 334 bortezomib plus rituximab treated patients), and serious adverse events (37 [11%] patients vs 59 [18%] patients) were lower in the rituximab group than in the combination group. The most common adverse events of grade 3 or higher were neutropenia (15 [4%] patients in the rituximab group and 37 [11%] patients in the bortezomib plus rituximab group), infection (15 [4%] patients and 36 [11%] patients, respectively), diarrhoea (no patients and 25 [7%] patients, respectively), herpes zoster (one [

Published
2011

7. Editorial

Author

Aby Lewin, Dror Meirow, Poliack A, Ben Yehuda D, E Rachmilewitz, J.G. Schenker, and Prus D

Subjects
Hodgkin s, medicine.medical_specialty, Pathology, business.industry, Ovarian tissue, General surgery, Reproductive medicine, Obstetrics and Gynecology, Disease, University hospital, humanities, Reproductive Medicine, Obstetrics and gynaecology, medicine, In patient, business
Abstract

Received August 15, 1997; revised and accepted January 2, 1998. Reprint requests: Dror Meirow, Department of Obstetrics and Gynecology, Hadassah University Hospital, P.O. Box 12000, Jerusalem, Israel (FAX: 00972-26434434). * Department of Obstetrics and Gynecology. 1 Department of Hematology. Department of Pathology. The opinions and commentary expressed in Editor's Corner articles are solely those of the author. Its publication does not imply endorsement by the Editor or American Society for Reproductive Medicine.

Published
1998

8. Biomarkers of response to ibrutinib plus nivolumab in relapsed diffuse large B-cell lymphoma, follicular lymphoma, or Richter's transformation

Author

Hodkinson, Brendan P. Oncology Translational Research (Estats Units d'Amèrica), Schaffer, Michael, Brody, Joshua D., Jurczak, Wojciech, Carpio Segura, Cecilia del Carmen, Ben-Yehuda, Dina, Avivi, Irit, Forslund, Ann, Özcan, Muhit, Alvarez, John, Ceulemans, Rob, Fourneau, Nele, Younes, Anas, Balasubramanian, Sriram, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Hodkinson BP, Schaffer M] Oncology Translational Research, Janssen Research & Development, Spring House, PA 19477, United States. [Brody JD] Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States. [Jurczak W] Department of Clinical Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, 31-115, Poland. [Carpio C] Servei d’Hematologia i hemoteràpia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Ben-Yehuda D] Department of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel, and Vall d'Hebron Barcelona Hospital Campus

Subjects
0301 basic medicine, Oncology, Limfomes, Original article, Cancer Research, medicine.medical_specialty, Non-hodgkin's lymphoma, Follicular lymphoma, neoplasias::neoplasias por tipo histológico::linfoma [ENFERMEDADES], Biological Factors::Biomarkers [CHEMICALS AND DRUGS], lcsh:RC254-282, Richter's transformation, factores biológicos::biomarcadores [COMPUESTOS QUÍMICOS Y DROGAS], Medicaments antineoplàstics, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Internal medicine, terapéutica::farmacoterapia::farmacoterapia combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Medicine, business.industry, Ibrutinib, Therapeutics::Drug Therapy::Drug Therapy, Combination [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Germinal center, Neoplasms::Neoplasms by Histologic Type::Lymphoma [DISEASES], lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Non-Hodgkin's lymphoma, Lymphoma, Nivolumab, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Marcadors bioquímics, Phase I/II trial, business, Diffuse large B-cell lymphoma, Biomarkers
Abstract

Highlights • Biomarkers of response to ibrutinib + nivolumab were analyzed in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma and Richter transformation. • DLBCL patients with elevated PD-L1 by immunohistochemistry tended to have better response and survival. • Whole exome sequencing identified gene mutations in alternate B-cell receptor pathways linked to response in DLBCL. • Enriched pathways by gene expression profiling were related to immune activation in responders and proliferation/replication in nonresponders. • This preliminary work may help to generate hypotheses on genetically defined subsets of patients most likely to benefit from ibrutinib + nivolumab., We analyzed potential biomarkers of response to ibrutinib plus nivolumab in biopsies from patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Richter's transformation (RT) from the LYM1002 phase I/IIa study, using programmed death ligand 1 (PD-L1) immunohistochemistry, whole exome sequencing (WES), and gene expression profiling (GEP). In DLBCL, PD-L1 elevation was more frequent in responders versus nonresponders (5/8 [62.5%] vs. 3/16 [18.8%]; p = 0.065; complete response 37.5% vs. 0%; p = 0.028). Overall response rates for patients with WES and GEP data, respectively, were: DLBCL (38.5% and 29.6%); FL (46.2% and 43.5%); RT (76.5% and 81.3%). In DLBCL, WES analyses demonstrated that mutations in RNF213 (40.0% vs. 6.2%; p = 0.055), KLHL14 (30.0% vs. 0%; p = 0.046), and LRP1B (30.0% vs. 6.2%; p = 0.264) were more frequent in responders. No responders had mutations in EBF1, ADAMTS20, AKAP9, TP53, MYD88, or TNFRSF14, while the frequency of these mutations in nonresponders ranged from 12.5% to 18.8%. In FL and RT, genes with different mutation frequencies in responders versus nonresponders were: BCL2 (75.0% vs. 28.6%; p = 0.047) and ROS1 (0% vs. 50.0%; p = 0.044), respectively. Per GEP, the most upregulated genes in responders were LEF1 and BTLA (overall), and CRTAM (germinal center B-cell–like DLBCL). Enriched pathways were related to immune activation in responders and resistance-associated proliferation/replication in nonresponders. This preliminary work may help to generate hypotheses regarding genetically defined subsets of DLBCL, FL, and RT patients most likely to benefit from ibrutinib plus nivolumab.

Published
2021

9. Panobinostat in Patients With Relapsed/Refractory Hodgkin's Lymphoma After Autologous Stem-Cell Transplantation: Results of a Phase II Study

Author

Simon J. Harrison, H. Miles Prince, Anna Sureda, Patrick B. Johnston, Dina Ben-Yehuda, Anas Younes, Pier Luigi Zinzani, Christophe Le Corre, Angela Shen, Andreas Engert, Tee Chuan Ong, Jennifer Gallagher, Mark Kirschbaum, Younes A, Sureda A, Ben-Yehuda D, Zinzani PL, Ong TC, Prince HM, Harrison SJ, Kirschbaum M, Johnston P, Gallagher J, Le Corre C, Shen A, and Engert A.

Subjects
Adult, Male, Oncology, Cancer Research, medicine.medical_specialty, Indoles, Adolescent, refractory Hodgkin's lymphoma, medicine.medical_treatment, Population, Administration, Oral, Phases of clinical research, Antineoplastic Agents, autologous stem-cell transplantation, Hematopoietic stem cell transplantation, Hydroxamic Acids, Disease-Free Survival, Young Adult, chemistry.chemical_compound, Autologous stem-cell transplantation, Recurrence, Panobinostat, Internal medicine, medicine, Humans, Treatment Failure, education, Aged, education.field_of_study, business.industry, Hematopoietic Stem Cell Transplantation, Hodgkin's lymphoma, medicine.disease, Hodgkin Disease, Surgery, Transplantation, Regimen, chemistry, Retreatment, Female, business
Abstract

Purpose Hodgkin's lymphoma (HL) has no standard of care for patients who are relapsed or refractory to autologous stem-cell transplantation (ASCT). This phase II study examined safety and activity of panobinostat in this population. Patients and Methods Panobinostat 40 mg was administered orally three times per week. The primary end point was objective response rate (ORR) based on investigator assessment of radiologic imaging. Secondary end points included ORR by independent central review, time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses were performed. Results The 129 treated patients (median age, 32 years; range, 18 to 75 years) were heavily pretreated with a median of four (range, two to seven) prior systemic regimens, and 41% did not respond to the regimen immediately preceding panobinostat. Tumor reductions occurred in 96 patients (74%). Objective response was achieved by 35 patients (27%), including 30 (23%) partial responses and five (4%) complete responses. The median TTR was 2.3 months, median DOR was 6.9 months, and median PFS was 6.1 months. The estimated 1-year overall survival rate was 78%. Common nonhematologic adverse events (AEs)—diarrhea, nausea, vomiting, and fatigue—were generally grade 1 and 2. Most common grade 3 and 4 hematologic AEs—thrombocytopenia, anemia, and neutropenia—were manageable. Early reductions in thymus and activation-regulated chemokine were observed in patients achieving complete or partial response. Conclusion In the largest, prospective, multicenter, international trial conducted in heavily pretreated patients with HL who relapsed or were refractory to ASCT, panobinostat monotherapy demonstrated antitumor activity, resulting in durable responses.

Published
2012

10. Autologous transplantation and maintenance therapy in multiple myeloma

Author

Antonio Palumbo, Federica Cavallo, Francesca Gay, Francesco Di Raimondo, Dina Ben Yehuda, Maria Teresa Petrucci, Sara Pezzatti, Tommaso Caravita, Chiara Cerrato, Elena Ribakovsky, Mariella Genuardi, Anna Cafro, Magda Marcatti, Lucio Catalano, Massimo Offidani, Angelo Michele Carella, Elena Zamagni, Francesca Patriarca, Pellegrino Musto, Andrea Evangelista, Giovannino Ciccone, Paola Omedé, Claudia Crippa, Paolo Corradini, Arnon Nagler, Mario Boccadoro, Michele Cavo, Palumbo, A, Cavallo, F, Gay, F, Di Raimondo, F, Ben Yehuda, D, Petrucci, Mt, Pezzatti, S, Caravita, T, Cerrato, C, Ribakovsky, E, Genuardi, M, Cafro, A, Marcatti, M, Catalano, L, Offidani, M, Carella, Am, Zamagni, E, Patriarca, F, Musto, P, Evangelista, A, Ciccone, G, Omedé, P, Crippa, C, Corradini, P, Nagler, A, Boccadoro, M, and Cavo, M.

Subjects
Adult, Melphalan, PREDNISONE, medicine.medical_specialty, Neutropenia, PLUS DEXAMETHASONE, BORTEZOMIB, Kaplan-Meier Estimate, Transplantation, Autologous, Disease-Free Survival, Maintenance Chemotherapy, Maintenance therapy, Antineoplastic Combined Chemotherapy Protocols, Humans, Medicine, Combined Modality Therapy, Autologous transplantation, Antineoplastic Agents, Alkylating, ELDERLY-PATIENTS, Multiple myeloma, Aged, Lenalidomide, LENALIDOMIDE, Autologous transplantation, multiple myeloma, business.industry, Hazard ratio, STEM-CELL TRANSPLANTATION, General Medicine, Middle Aged, RANDOMIZED CONTROLLED-TRIAL, medicine.disease, INDUCTION THERAPY, Thalidomide, Surgery, Consolidation Chemotherapy, Transplantation, INITIAL TREATMENT, MELPHALAN, Multiple Myeloma, business, Stem Cell Transplantation, medicine.drug
Abstract

BACKGROUND: This open-label, randomized, phase 3 study compared melphalan at a dose of 200 mg per square meter of body-surface area plus autologous stem-cell transplantation with melphalan-prednisone-lenalidomide (MPR) and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma. METHODS: We randomly assigned 273 patients 65 years of age or younger to high-dose melphalan plus stem-cell transplantation or MPR consolidation therapy after induction, and 251 patients to lenalidomide maintenance therapy or no maintenance therapy. The primary end point was progression-free survival. RESULTS: The median follow-up period was 51.2 months. Both progression-free and overall survival were significantly longer with high-dose melphalan plus stem-cell transplantation than with MPR (median progression-free survival, 43.0 months vs. 22.4 months; hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.32 to 0.61; P

Published
2014

11. International Myeloma Working Group recommendations for global myeloma care

Author

Roman Hájek, R. L. Powles, Artur Jurczyszyn, V. Hungria, Heinz Ludwig, Douglas E. Joshua, W Ming Chen, J. S. Miguel, J. Hou, Suzanne Lentzsch, K. Shimizu, Antonio Palumbo, E. Terpos, A Rodriguez Morales, Elena Zamagni, R. García Sanz, Meletios A. Dimopoulos, Dina Ben-Yehuda, Brian G.M. Durie, Pia Sondergeld, K Romeril, Ludwig, H, Miguel, J, Dimopoulos, Ma, Palumbo, A, Garcia Sanz, R, Powles, R, Lentzsch, S, Ming Chen, W, Hou, J, Jurczyszyn, A, Romeril, K, Hajek, R, Terpos, E, Shimizu, K, Joshua, D, Hungria, V, Rodriguez Morales, A, Ben-Yehuda, D, Sondergeld, P, Zamagni, E, and Durie, B

Subjects
Cancer Research, Pathology, medicine.medical_specialty, business.industry, Treatment outcome, MEDLINE, Hematology, Disease, medicine.disease, Minimal residual disease, Clinical Practice, Treatment Outcome, Oncology, Recurrence, medicine, Humans, business, Intensive care medicine, Multiple Myeloma, Multiple myeloma, Monitoring, Physiologic, multiple myeloma, recommendations
Abstract

Recent developments have led to remarkable improvements in the assessment and treatment of patients with multiple myeloma (MM). New technologies have become available to precisely evaluate the biology and extent of the disease, including information about cytogenetics and genetic abnormalities, extramedullary manifestations and minimal residual disease. New, more effective drugs have been introduced into clinical practice, which enable clinicians to significantly improve the outcome of patients but also pose new challenges for the prevention and management of their specific side effects. Given these various new options and challenges, it is important to identify the minimal requirements for diagnosis and treatment of patients, as access to the most sophisticated advances may vary depending on local circumstances. Here, we propose the minimal requirements and possible options for diagnosis, monitoring and treatment of patients with multiple myeloma.

Published
2014

12. A randomized, open-label, multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine, cyclophosphamide and rituximab versus fludarabine, cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia

Author

Awan, Farrukh T, Hillmen, Peter, Hellmann, Andrzej, Robak, Tadeusz, Hughes, Steven G., Trone, Denise, Shannon, Megan, Flinn, Ian W., Byrd, John C., Riveros, Dardo, Pavlovsky, Santiago, Iastrebner, Claudio M., Carney, Dennis A., Deveridge, Sandra, Durrant, Simon, Hahn, Uwe H., Hertzberg, Mark, Leahy, Michael F., David, Ma, Marlton, Paula, Mulligan, Stephen, Opat, Stephen S., Tiley, Campbell, Wickham, Nicholas W., Cannell, Paul, Gatalano, John, Catalano, John, Cull, Gavin, Luen B., To, Hopfinger, Georg, Jager, Ulrich, Linkesch, Werner, Petzer, Andreas, Schwarzmeier, Josef, Steurer, Michael, Greil, Richard, Bememan, Zwi, Bosly, Andre, Bron, Dominique, Janssens, Ann, Offner, Fritz, Van Den Neste, Eric W., Ka Lung, Wu, Van Hoof, Achiel, Maiolino, Angelo, Pinczowski, Helio, Zanichelli, Maria A., Pereira, Juliana, Larratt, Loree, Spaner, David, Howson Jan, Kang, Chen, Christine I., Cantin, Guy, Fernandez, Louis A., Fraser, Graeme, Mayer, Jiri, Trneny, Marek, Jebavy, Ladislav, Bordessoule, Dominique, Lamy, Thierry, Milpied, Noel, Truchan Graczyk, Malgorzata, Eghbali, Houchingue, Karsenti, Jean Michel, Celigny, Philippe Solal, Mans, Le, Cazin, Bruno, Gyan, Emmanuel, Lepretre, Stephane, Bergmann, Lothar, Tsionos, Konstantinos, Lokeshwar, Nilesh M., Agarwal, Mohan B., Ross, Cecil R., Deshmukh, Chetan D., Narayanan, Geetha, Raina, Vinod, Bondarde, Shailesh A., Shah, Bhavin A., Bairey, Osnat, Tikva, Petach, Shvidel, Lev, Ambrosetti, Achille, Rossi, Policlinico G. B., Angelucci, Emanuele, Carella, Angelo M., Massaia, Massimo, Zinzani, Pier L., Caligaris Cappio, Federico, Foa, Roberto, Gaidano, Gianluca, della Caritá, A. O. Maggiore, Leone, Giuseppe, Santoro, Armando, Griskevicius, Laimonas, Jurgutis, Romualdas, Baker, Bartrum W., Hawkins, Timothy, Corbett, Gillian M., Ganly, Peter, D'Souza, Alvyn B., Deptala, Andrzej, Holowiecki, Jerzy, Kloczko, Janusz, Skotnicki, Aleksander, Zdziarska, Barbara, Kyrcz Krzemien, Slawomira, Dmoszynska, Anna, Moreira, Anna, Pereira, Ana P., Colita, Andrei, Moicean, Andreea D., Vasilica, Mariana, Danaila, Catalin, Gheorghita, Emanuil, Pavlov, Vyacheslav V., Rossiev, Viktor A., Konstantinova, Tatiana, Samoilova, Olga S., Novgorod, Nizhniy, Shelekhova, Tatyana, Zaritsky, Andrey Y., Abdulkadyrov, Kudrat M., Zyuzgin, Ilya S., Pristupa, Alexander S., Loscertales, Javier, Vidal, Joan Besalduch, de Mallorca, Palma, Gonzalez, Marcos, Ortuno, Francisco, Giraldo, Pilar, Nathwani, Amit, Agrawal, Samir G., Rule, Simon, Dearden, Claire E., Bloor, Adrian J., Haynes, Andrew, Singer, Charles, Boclek, Robert G., Bosserman, Linda D., Chan, David, Davidson, Sheldon J., Dichmann, Robert A., Farber, Charles, Hart, Lowell, Hermann, Robert, Eddie, Hu, Janakiraman, Nalini, Jonas, William, Liem, Kiem D., Mcintyre, Rosemary E., O'Brien, Susan, Patel, Giribala, Rado, Thomas, Schilder, Russell, Smith, Scott E., Stock, Wendy, Turturro, Francesco, Venugopal, Parameswaran, Anderson, Thomas C., Berry, William, Boyd, Thomas E., Byrd, John, Cooper, Maureen, Flinn, Ian, Gersh, Robert, Gordon, David, Guzley, Gregory J., Wilks, Sharon T., Klein, Andreas, Krauss, John C., Lister, John, Mandell, Lance, Molina, Arthur, Cooper, Barry, Pendergrass, Kelly B., Reeder, Craig, Savin, Michael A., Spitzer, Gary, Tuscano, Joseph M., Vandeventer, Hendrik, Eradat, Herbert A., Masood, Aisha, Mena, Raul, F. T. Awan, P. Hillmen, A. Hellmann, T. Robak, S. G. Hughe, D. Trone, M. Shannon, I. W. Flinn, J. C. Byrd, L. U. C., and Riveros D, Iastrebner CM, Carney DA, Deveridge S, Durrant S, Hahn UH, Hertzberg M, Leahy MF, Ma D, Marlton P, Mulligan S, Opat SS, Tiley C, Wickham NW, Cannell P, Gatalano J, Cull G, B To L, Catalano J, Wickham NW, Hopfinger G, Jager U, Linkesch W, Petzer A, Schwarzmeier J, Steurer M, Greil R, Bememan Z, Bosly A, Bron D, Janssens A, Offner F, Van Den Neste EW, Wu KL, Van Hoof A, Maiolino A, Pinczowski H, Zanichelli MA, Pereira J, Larratt L, Spaner D, Howson-Jan K, Chen CI, Fernandez LA, Fraser G, Mayer J, Trneny M, Jebavy L, Bordessoule D, Lamy T, Milpied N, Eghbali H, Karsenti JM, Celigny PS, Cazin B, Gyan E, Lepretre S, Bergmann L, Tsionos K, Lokeshwar NM, Agarwal MB, Ross CR, Deshmukh CD, Narayanan G, Raina V, Bondarde SA, Shah BA, Bairey O, Ben-Yehuda D, Shvidel L, Ambrosetti A, Angelucci E, Carella AM, Massaia M, Zinzani PL, Caligaris-Cappio F, Foa R, Gaidano G, Leone G, Santoro A, Griskevicius L, Jurgutis R, Baker BW, Hawkins T, Corbett GM, Ganly P, D'Souza AB, Deptala A, Hellmann A, Holowiecki J, Kloczko J, Skotnicki A, Zdziarska B, Robak T, Dmoszynska A, Moreira I, Pereira AP, Colita A, Moicean AD, Gheorghita E, Vasilica M, Pavlov VV, Rossiev VA, Konstantinova T, Samoilova OS, Novgorod N, Shelekhova T, Zaritsky AY, Abdulkadyrov KM, Zyuzgin IS, Pristupa AS, Loscertales J, Casado LF, Gonzalez M, Ortuno F, Giraldo P, Servet M, Nathwani A, Howson-Jan K, Agrawal SG, Hillmen P, Rule S, Dearden CE, Bloor AJ, Haynes A, Singer C, Boclek RG, Bosserman LD, Chan D, Davidson SJ, Dichmann RA, Farber C, Guzley GJ, Hermann R, Hu E, Janakiraman N, Jonas W, Liem KD, Mcintyre RE, O'Brien S, Patel G, Rado T, Schilder R, Smith SE, Stock W, Turturro F, Venugopal P, Berry W, Boyd TE, Byrd J, Cooper M, Flinn I, Gersh R, Gordon D, Wilks ST, Klein A, Krauss JC, Lister J, Mandell L, Molina A, Pendergrass KB, Reeder C, Savin MA, Spitzer G, Tuscano JM, van Deventer H, Eradat HA, Cooper B, Masood A, Mena R.

Subjects
Oncology, Male, Chronic lymphocytic leukaemia, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Pharmacology, Antibodies, Monoclonal, Murine-Derived, Recurrence, hemic and lymphatic diseases, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, 80 and over, Medicine, drug therapy, Male, Middle Aged, Recurrence, Vidarabine, Chronic, Aged, 80 and over, Leukemia, Medicine (all), Antibodies, Monoclonal, Hematology, Middle Aged, Adult, Aged, Aged, Lymphocytic, Fludarabine, Tolerability, Small lymphocytic lymphoma, administration /&/ dosage/adverse effects, Female, Humans, Leukemia, Rituximab, Female, Vidarabine, medicine.drug, Adult, Murine-Derived, medicine.medical_specialty, Cyclophosphamide, chemical and pharmacologic phenomena, CD23, Lumiliximab, Aged, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Antibodies, chronic lymphocytic leukaemia, lumiliximab, small lymphocytic lymphoma, Internal medicine, administration /&/ dosage/adverse effects/analogs /&/ derivatives, 80 and over, Antibodie, Adverse effect, Lymphocytic leukaemia, business.industry, administration /&/ dosage/adverse effects, Antibodie, B-Cell, administration /&/ dosage/adverse effects, Cyclophosphamide, Interim analysis, administration /&/ dosage/adverse effects, Antineoplastic Combined Chemotherapy Protocol, business
Abstract

Item does not contain fulltext Lumiliximab is a chimeric monoclonal antibody that targets CD23 on the surface of chronic lymphocytic leukaemia (CLL) B-cells. Early phase clinical studies with lumiliximab alone and in combination with fludarabine, cyclophosphamide and rituximab (FCR) established its potential efficacy and tolerability. The 152CL201 trial [Lumiliximab with fludarabine, cyclophosphamide and rituximab (FCR) versus FCR alone in subjects with relapsed CLL; LUCID] was a phase 2/3, randomized (1:1), open-label, multicentre study of lumiliximab in combination with FCR versus FCR alone in patients with relapsed CLL. Six hundred and twenty-seven patients were randomized to either arm. Overall the combination of lumiliximab with FCR was not significantly better than FCR alone (overall response rate 71% vs. 72%, complete response rate 16% vs. 15%, median progression-free survival 24.6 vs. 23.9 months respectively, for FCR with and without lumiliximab). There was a slightly increased incidence of adverse events with lumiliximab but these increases did not appear to lead to differences in eventual outcomes. An interim analysis failed to show sufficient efficacy of the combination of lumiliximab with FCR. The study was therefore stopped early for lack of efficacy. Despite the eventual outcome, the LUCID trial is one of the largest studies that provides valuable insight into the efficacy and tolerability of FCR as a therapeutic option for patients with relapsed CLL.

Published
2014

13. Continuous lenalidomide treatment for newly diagnosed multiple myeloma

Author

Palumbo, Antonio, Roman Hajek, Delforge, Michel, Kropff, Martin, Petrucci, Maria Teresa, Catalano, John, Gisslinger, Heinz, Wiktor-Jedrzejczak, Wieslaw, Zodelava, Mamia, Weisel, Katja, Cascavilla, Nicola, Iosava, Genadi, Cavo, Michele, Kloczko, Janusz, Blade, Joan, Beksac, Meral, Spicka, Ivan, Plesner, Torben, Radke, Joergen, Langer, Christian, Ben Yehuda, Dina, Corso, Alessandro, Herbein, Lindsay, Yu, Zhinuan, Mei, Jay, Jacques, Christian, Dimopoulos, Meletios A., Mm-, Investigators, Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jędrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J, Bladé J, Beksac M, Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA, and MM-015 Investigators.

Subjects
Melphalan, Male, medicine.medical_specialty, Neutropenia, Administration, Oral, Kaplan-Meier Estimate, Gastroenterology, Disease-Free Survival, Maintenance Chemotherapy, 03 medical and health sciences, 0302 clinical medicine, MULTIPLE MYELOMA, Double-Blind Method, immune system diseases, Internal medicine, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Medicine, Humans, cardiovascular diseases, Lenalidomide, neoplasms, Multiple myeloma, Aged, Aged, 80 and over, business.industry, Hazard ratio, Induction chemotherapy, Neoplasms, Second Primary, General Medicine, Induction Chemotherapy, medicine.disease, 3. Good health, Surgery, Thalidomide, Transplantation, surgical procedures, operative, 030220 oncology & carcinogenesis, Prednisone, Female, business, Multiple Myeloma, 030215 immunology, medicine.drug, Follow-Up Studies
Abstract

BACKGROUND: Lenalidomide has tumoricidal and immunomodulatory activity against multiple myeloma. This double-blind, multicenter, randomized study compared melphalan-prednisone-lenalidomide induction followed by lenalidomide maintenance (MPR-R) with melphalan-prednisone-lenalidomide (MPR) or melphalan-prednisone (MP) followed by placebo in patients 65 years of age or older with newly diagnosed multiple myeloma. METHODS: We randomly assigned patients who were ineligible for transplantation to receive MPR-R (nine 4-week cycles of MPR followed by lenalidomide maintenance therapy until a relapse or disease progression occurred [152 patients]) or to receive MPR (153 patients) or MP (154 patients) without maintenance therapy. The primary end point was progression-free survival. RESULTS: The median follow-up period was 30 months. The median progression-free survival was significantly longer with MPR-R (31 months) than with MPR (14 months; hazard ratio, 0.49; P

Published
2012

14. A phase II multicenter study of troxacitabine in relapsed or refractory lymphoproliferative neoplasm or multiple myeloma

Author

Renato Fanin, Julie M. Vose, Michele Baccarani, Robert Bélanger, Stephanie A. Gregory, Bertrand Coiffier, Thierry Facon, Amit Panwalkar, Dolores Caballero, Dina Ben-Yehuda, Francis J. Giles, Vose JM, Panwalkar A, Belanger R, Coiffier B, Baccarani M, Gregory SA, Facon T, Fanin R, Caballero D, Ben-Yehuda D, and Giles F.

Subjects
Adult, Male, Oncology, Cancer Research, medicine.medical_specialty, Lymphoma, Troxacitabine, Lymphoproliferative disorders, Antineoplastic Agents, Models, Biological, Cytosine, Refractory, Recurrence, Internal medicine, medicine, Humans, Multiple myeloma, Aged, Salvage Therapy, Leukemia, Study drug, Dose-Response Relationship, Drug, business.industry, Dioxolanes, Hematology, Middle Aged, medicine.disease, Survival Analysis, Phase i study, Treatment Outcome, Multicenter study, Drug Resistance, Neoplasm, Immunology, Female, Multiple Myeloma, business, medicine.drug
Abstract

Options for patients with relapsed/refractory lymphoproliferative disorders and multiple myeloma are currently limited. Troxacitabine has shown promise in preclinical studies in a variety of malignancies; hence, the current study was conducted to evaluate the activity of troxacitabine in relapsed or refractory lymphoid malignancies. This was a phase II, open-label, multinational, multicenter study of patients with relapsed or refractory lymphoproliferative disorders or multiple myeloma. Thirty-four adults were enrolled in the study and received the study drug at either 5.4 mg/m2 (n = 16) or 4.3 mg/m2 (n = 18). The dose was decided in a phase I study, during which dose escalation was carried to reach a maximum tolerated dose with an acceptable toxicity profile. Two separate phase I studies were performed in Europe and the US. Troxacitabine was administered by intravenous infusion over 30 min daily for days 1 - 5 every 4 weeks. Treatment was continued to disease progression or until the subjects met criteria for withdrawal or unacceptable toxicities were evident as outlined in the protocol. Two patients had a partial response (PR) to treatment with troxacitabine to yield an overall response rate of 13%. There were no complete responses seen with the drug. Stable disease was achieved in 15 patients (44%). All patients had at least one treatment related adverse event, which led to six withdrawals from the study. Hematologic toxicity constituted the most common adverse events. Serious adverse effects were seen in 62% of patients. None of the 13 deaths were attributed directly to troxacitabine. As a single agent, troxacitabine has limited benefit in patients with advanced lymphoproliferative disorders or multiple myeloma. Future studies will be needed to address modified dosing according to emerging pharmacokinetic and pharmacodynamic data and combination therapy which may lead to improved clinical benefit for troxacitabine in hematologic malignancies.

Published
2007

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