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A better angel of our nature: Hanna Michel “Jean” Khoury, MD (April 24, 1967-May 22, 2017)

2017; Wiley; Volume: 123; Issue: 16 Linguagem: Inglês

10.1002/cncr.30847

1097-0142

Fadlo R. Khuri,

Family Support in Illness

Jean Khoury was a man full of passion, full of life, and resplendent with the courage to take life on in all its complexity. He was the physician's physician, the mentor's mentor, a wonderful father and husband, a man in full in the best sense of the phrase. He was an incredibly close friend, and always seemed to be the epitome of cool. Try explaining to yourself when you're trying to simply color coordinate your jacket, tie, pants, and shirt, or getting through a day when you have 25 patients in a clinic, how a man with such infinite grace could glide through life and seem to never ever break a sweat, and see 50 patients in just over half the time. Except that Hanna never glided through life, and that impression frustrated him. He was smart, thoughtful, kind, athletic, patient, analytic, loving, precise, and absolutely possessed of a remarkable judgment, especially with regard to people. Here was a tremendous difference with Hanna that so few people can contemplate, much less achieve. Hanna took his time with people, and sought to extract from them their greatest qualities. He used his generosity of spirit and analytic will to turn their weaknesses into strengths, their hopes into dreams. He even sought to turn their nightmares, such as those we face with the dreaded disease that we treat and that he ultimately succumbed to after a ferocious battle, into meaningful moments of rare grace. Hanna attended the Jesuit Facultés Universitaires Notre-Dame de la Paix in Namur, Belgium, for his undergraduate degree, and the Université catholique de Louvain in Brussels, where he received his medical degree. He completed his residency in internal medicine at Memorial University Medical Center in Savannah, Georgia, and his fellowship in hematology-oncology as well as a bone marrow transplantation fellowship at the Washington University School of Medicine in St. Louis, Missouri. I first met Hanna in December of 2003 when he was serving on the faculty at Washington University. Ned Waller, the head of Emory University's Section of Blood and Bone Marrow Transplantation, had come back from a visit to St. Louis absolutely convinced we had found our future Chief of Hematology. So I attended the annual American Society of Hematology meeting for the first time since my fellowship, and was quite impressed with the person I met. His track record on paper and clinical references were impressive by themselves, but what was even more startling was the quiet demeanor, the courageous but humble mien, the nuanced but decisive responses to the real challenges academic medicine faced with mentoring high-quality individuals in the physician-scientist mold without sacrificing the quality of the patient encounter. I recognized by the end of our meeting that I had rarely been so quickly convinced by anyone. Emory University, and I, had found our transformative new Chief of Hematology in this still 36-year-old man, barely 4 years after he completed his training. After coming to Emory University, Hanna led and completely revitalized the Division of Hematology and the Leukemia Program of the Winship Cancer Institute. Hanna loved people, but he lived to push them out of their comfort zones. An incredible athlete, both mentally and physically, he would occasionally back off after disrupting to a certain degree, and come over to my office almost apologetically to ask if he was causing too much trouble. But he always went back for more. He designed the physical space of the Division of Hematology; recruited folks for the division from young stars to senior leaders; and was an equal opportunity mentor to nurses, staff, medical students, residents, fellows, junior faculty, senior faculty, and especially his always beleaguered chair, who would repeatedly be lulled into thinking that the great Jean Khoury was coming by to ask for help in solving his challenges, when all along he was coming to solve my own challenges. His extraordinary skill and compassion as a physician, as a clinical investigator, and as a mentor led to many accolades and awards, including being selected as the first holder of the R. Randall Rollins Chair in Oncology, and election to the Alpha Omega Alpha Honor Medical Society. He served with distinction in several major international leadership roles at the American Society for Blood and Marrow Transplantation and the American Society of Hematology, and was Section Editor for Hematologic Malignancies for Cancer for the last 5 years. He won the teacher of the year award at both the Washington University and Emory University Schools of Medicine, in the first case outcompeting top senior faculty while he was still an instructor of medicine, an unheard-of feat of mentorship. And the equal opportunity mentorship would continue: nurses and nurse practitioners, senior and junior faculty from all departments, fellows, medical students, physician assistants, and even undergraduates all came under his matchless tutelage. In his clinical and research work, he was a pioneer in the molecular targeting of leukemias. His focus was in the areas of drug development in bone marrow transplantation, leukemia, and myelodysplasia. He worked at the intersection of the laboratory and the clinic on new approaches for the prevention and treatment of acute graft-versus-host disease, and the identification of genetic markers that predict outcomes in patients with hematological cancers. He established the leukemia tissue bank at Washington University and the hematology tissue bank at Emory University. He published as first, senior, or coauthor more than 140 peer-reviewed articles in high-impact journals such as The New England Journal of Medicine, Cancer Cell, Nature Communications, the Journal of Clinical Oncology, and Blood (see selected list below). He conducted more than 50 phase 1, 2, and 3 clinical trials. He was leading an absolutely stellar new group focused on chronic myelogenous leukemia (now and forever named the H. Jean Khoury Cure CML Consortium) along with the best and the brightest thought leaders in the field at the time he became ill, and continued the work to within a week of his death. When I finally accepted the job as president of the American University of Beirut (AUB), Hanna was among the very first to know. This was not only because he is, was, and always will be one of the closest friends that I have ever made. But I knew the anxiety that this would provoke in him. You see, Jean had grown up under the shadow of the Lebanese Civil War, and would spend days on end in the bomb shelter of their building. One thing that could provoke anxiety in this serene man was the prospect of moving back to Lebanon now, especially when he, Angela, Mikhail, Iman, and Alya had found a delicate but durable slice of peace, prosperity, and creativity at Emory University, in the rolling hills of one of America's most beautiful cities. He was incredibly proud of and attached to everything that we as a family of physicians, scientists, nurses, trainees, staff, and yes, especially patients, had built at Emory University and the Winship Cancer Institute. He was going to change the world from Winship, from Emory. So I talked to him at length and reassured him that now was not his time to come back to Lebanon: “One day,” I said, “but not now. You are doing too much good. Unlike me, or almost anyone else here, or anyone else anywhere, you are simply too irreplaceable in too many people's lives.” Jean came to my inauguration in Beirut. Less than 6 weeks after he had proudly given our AUB, Emory University, The University of Texas MD Anderson Cancer Center, University of Colorado, Harvard/Dana-Farber Cancer Institute, and University of Wisconsin crowd a tour of the history and beauty of Beirut, culminating in a precelebration dinner soirée in his apartment, I got a message from him that filled me with dread. Always polite, my friend, the erudite and poised professor, asked me to call him as soon as possible. As soon as I saw the message, I called him, and he and Angela told me he had esophageal cancer. Over the next 14.5 months, Hanna Khoury, 4-Dan black belt in Taekwando, musical cognoscenti, master physician, scientist, teacher, and scholar, fought back with everything he had. The ultimate physician, scholar, and mentor, a man given to provoking, coaching, and producing the very best from everyone, bore his challenges with a smile and, remarkably, until his last day, set about to console all around him with his grace, humor, and the shining example of a man who really was, in the immortal words of Lincoln, one of those rare “better angels of our nature.” Hanna Michel “Jean” Khoury passed away at 9:00 AM on May 22, 2017, with his wife Angela and his children Mikhail, Iman, and Alya beside him. But his words, actions, and ideals will long outlive him. I will remember him always smiling, occasionally sarcastically, pushing, prodding, and enabling people to live their dreams, to tap their potential. Celebrate the beauty of life, he said so often, and leave a real piece of yourself behind. He definitely did, with each and every one of us and with thousands of people more. He really was a master physician, and a matchless friend. May God bless and keep you always May your wishes all come true May you always do for others And let others do for you May you build a ladder to the stars And climb on every rung May you stay forever young Farewell, my faithful and farsighted friend. 1. Khoury, H, Adkins, D, Brown, R, Trinkaus, K, Vij, R, Miller, G, Goodnough, LT, DiPersio, J. Does early treatment with high-dose methylprednisolone alter the course of hepatic regimen-related toxicity? Bone Marrow Transplant. 2000; 25: 337- 743. 2. Khoury, H, Kashyap, A, Adkins, DR, Brown, RA, Miller, G, Vij, R, Westervelt, P, Trinkaus, K, Goodnough, LT, Hayashi, RJ, Parker, P, Forman, SJ, DiPersio, JF. Treatment of steroid-resistant acute graft-versus-host disease with anti-thymocyte globulin. Bone Marrow Transplant. 2001; 27: 1059- 1064. 3. Khoury, HJ, Loberiza, FR, Ringden, O, Barrett, AJ, Bolwell, BJ, Cahn, JY, Champlin, RE, Gale, RP, Hale, GA, Urbano-Ispizua, A, Martino, R, McCarthy, PL, Tiberghien, P, Verdonck, LF, Horowitz, MM. Impact of posttransplantation G-CSF on outcomes of allogeneic hematopoietic stem cell transplantation. Blood. 2006; 107: 1712- 1716. 4. Kang, S, Dong, S, Gu, TL, Guo, A, Cohen, MS, Lonial, S, Khoury, HJ, Fabbro, D, Gilliland, DG, Bergsagel, PL, Taunton, J, Polakiewicz, RD, Chen, J. FGFR3 activates RSK2 to mediate hematopoietic transformation through tyrosine phosphorylation of RSK2 and activation of the MEK/ERK pathway. Cancer Cell. 2007; 12: 201- 214. 5. Lima, L, Bernal-Mizrachi, L, Saxe, D, Mann, KP, Tighiouart, M, Arellano, M, Heffner, L, McLemore, M, Langston, A, Winton, E, Khoury, HJ. Peripheral blood monitoring of chronic myeloid leukemia during treatment with imatinib, second-line agents, and beyond. Cancer. 2011; 117: 1245- 1252. 6. Arellano, M, Winton, E, Pan, L, Lima, L, Tighiouart, M, Bhalla, K, Heffner, LT, Neely, J, Hutcherson, D, McLemore, M, Langston, A, Khoury, HJ. High-dose cytarabine induction is well tolerated and active in patients with de novo acute myeloid leukemia older than 60 years. Cancer. 2012; 118: 428- 433. 7. Khoury, HJ, Garcia-Manero, G, Borthakur, G, Kadia, T, Foudray, MC, Arellano, M, Langston, A, Bethelmie-Bryan, B, Rush, S, Litwiler, K, Karan, S, Simmons, H, Marcus, AI, Ptaszynski, M, Kantarjian, H. A phase 1 dose-escalation study of ARRY-520, a kinesin spindle protein inhibitor, in patients with advanced myeloid leukemias. Cancer. 2012; 118: 3556- 3564. 8. Antun, AG, Gleason, S, Arellano, M, Langston, AA, McLemore, ML, Gaddh, M, el Rassi, F, Bernal-Mizrachi, L, Galipeau, J, Heffner, LT, Winton, EF, Khoury, HJ. Epsilon aminocaproic acid prevents bleeding in severely thrombocytopenic patients with hematological malignancies. Cancer. 2013; 119: 3784- 3787. 9. Cortes, JE, Kim, DW, Pinilla-Ibarz, J, le Coutre, P, Paquette, R, Chuah, C, Nicolini, FE, Apperley, JF, Khoury, HJ, Talpaz, M, DiPersio, J, DeAngelo, DJ, Abruzzese, E, Rea, D, Baccarani, M, Muller, MC, Gambacorti-Passerini, C, Wong, S, Lustgarten, S, Rivera, VM, Clackson, T, Turner, CD, Haluska, FG, Guilhot, F, Deininger, MW, Hochhaus, A, Hughes, T, Goldman, JM, Shah, NP, Kantarjian, H; PACE Investigators. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013; 369: 1783- 1796. 10. Zabriskie, MS, Eide, CA, Tantravahi, SK, Vellore, NA, Estrada, J, Nicolini, FE, Khoury, HJ, Larson, RA, Konopleva, M, Cortes, JE, Kantarjian, H, Jabbour, EJ, Kornblau, SM, Lipton, JH, Rea, D, Stenke, L, Barbany, G, Lange, T, Hernandez-Boluda, JC, Ossenkoppele, GJ, Press, RD, Chuah, C, Goldberg, SL, Wetzler, M, Mahon, FX, Etienne, G, Baccarani, M, Soverini, S, Rosti, G, Rousselot, P, Friedman, R, Deininger, M, Reynolds, KR, Heaton, WL, Eiring, AM, Pomicter, AD, Khorashad, JS, Kelley, TW, Baron, R, Druker, BJ, Deininger, MW, O'Hare, T. BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia. Cancer Cell. 2014; 26: 428- 442. 11. Ma, L, Shan, Y, Bai, R, Xue, L, Eide, CA, Ou, J, Zhu, LJ, Hutchinson, L, Cerny, J, Khoury, HJ, Sheng, Z, Druker, BJ, Li, S, Green, MR. A therapeutically targetable mechanism of BCR-ABL-independent imatinib resistance in chronic myeloid leukemia. Sci Transl Med. 2014; 6: 252ra121. 12. Cortes, JE, Kantarjian, HM, Rea, D, Wetzler, M, Lipton, JH, Akard, L, Khoury, HJ, Michallet, M, Guerci-Bresler, A, Chuah, C, Hellmann, A, Digumarti, R, Parikh, PM, Legros, L, Warzocha, K, Baccarani, M, Li, E, Munteanu, EM, Nicolini, FE. Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic- or accelerated-phase chronic myeloid leukemia: results with 24 months of follow-up. Cancer. 2015; 121: 1637- 1644. 13. Lin, R, Elf, S, Shan, C, Kang, HB, Ji, Q, Zhou, L, Hitosugi, T, Zhang, L, Zhang, S, Seo, JH, Xie, J, Tucker, M, Gu, TL, Sudderth, J, Jiang, L, Mitsche, M, DeBerardinis, RJ, Wu, S, Li, Y, Mao, H, Chen, PR, Wang, D, Chen, GZ, Hurwitz, SJ, Lonial, S, Arellano, ML, Khoury, HJ, Khuri, FR, Lee, BH, Lei, Q, Brat, DJ, Ye, K, Boggon, TJ, He, C, Kang, S, Fan, J, Chen, J. 6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling. Nat Cell Biol. 2015; 17: 1484- 1496. 14. Deol, A, Sengsayadeth, S, Ahn, KW, Wang, HL, Aljurf, M, Antin, JH, Battiwalla, M, Bornhauser, M, Cahn, JY, Camitta, B, Chen, YB, Cutler, CS, Gale, RP, Ganguly, S, Hamadani, M, Inamoto, Y, Jagasia, M, Kamble, R, Koreth, J, Lazarus, HM, Liesveld, J, Litzow, MR, Marks, DI, Nishihori, T, Olsson, RF, Reshef, R, Rowe, JM, Saad, AA, Sabloff, M, Schouten, HC, Shea, TC, Soiffer, RJ, Uy, GL, Waller, EK, Wiernik, PH, Wirk, B, Woolfrey, AE, Bunjes, D, Devine, S, Lima, M, Sandmaier, BM, Weisdorf, D, Khoury, HJ, Saber, W. Does FLT3 mutation impact survival after hematopoietic stem cell transplantation for acute myeloid leukemia? A Center for International Blood and Marrow Transplant Research (CIBMTR) analysis. Cancer. 2016; 122: 3005- 3014. 15. Fan, J, Lin, R, Xia, S, Chen, D, Elf, SE, Liu, S, Pan, Y, Xu, H, Qian, Z, Wang, M, Shan, C, Zhou, L, Lei, QY, Li, Y, Mao, H, Lee, BH, Sudderth, J, DeBerardinis, RJ, Zhang, G, Owonikoko, T, Gaddh, M, Arellano, ML, Khoury, HJ, Khuri, FR, Kang, S, Doetsch, PW, Lonial, S, Boggon, TJ, Curran, WJ, Chen, J. Tetrameric acetyl-CoA acetyltransferase 1 is important for tumor growth. Mol Cell. 2016; 64: 859- 874. 16. Kong, JH, Winton, EF, Heffner, LT, Chen, Z, Langston, AA, Hill, B, Arellano, M, El-Rassi, F, Kim, A, Jillella, A, Kota, VK, Bodo, I, Khoury, HJ. Does the frequency of molecular monitoring after tyrosine kinase inhibitor discontinuation affect outcomes of patients with chronic myeloid leukemia? [published online ahead of print February 27, 2017]. Cancer. doi:10.1002/cncr.30608.