A Keen Mind and a Daring Spirit Propel Kantarjian's Many Discoveries in Leukemia Therapy

Hagop M. Kantarjian, MD

Hagop M. Kantarjian, MD, has built the nation’s largest clinical leukemia practice, in part to ensure that leukemia studies are completed efficiently and in a timely manner. This helped him become one of the most productive clinical translational cancer researchers of all time.

“My clinic is my research laboratory, and nearly every patient is participating in a study,” he said. “The goal is to give patients something better than current standards of care and then, when the regimens we devise become standards of care, to look for regimens that are even better.”

This attitude has revolutionized the treatment of many types of leukemia, extending the lives not only of many thousands who have come to the leukemia program at MD Anderson Cancer Center in Houston, Texas, but also of millions who have received care elsewhere.

Kantarjian spent decades developing the new research protocols that transformed chronic myeloid leukemia (CML) from a death sentence to a manageable condition. He helped create the hyper-cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) regimen for treating acute lymphocytic leukemia (ALL) in adults. He found lifesaving uses for drugs that had been abandoned, important medications such as clofarabine (Clolar) and decitabine (Dacogen). He pioneered the use of epigenetic therapy in leukemia.

Photographic, Encyclopedic Memory

In all, Kantarjian has authored or coauthored more than 1200 peer-reviewed articles, many of them describing breakthrough studies that rank among the most important in the history of leukemia research.Why has Kantarjian achieved so much success? Colleagues say it starts with remarkable mental talents.

“He has a photographic, encyclopedic memory unlike any other I’ve ever encountered. He can absorb huge quantities of information and remember it all forever,” said another giant of cancer research, Emil J. Freireich, MD.

According to Freireich, who helped invent the very idea of combination chemotherapy, Kantarjian’s incredible facility for acquiring, storing, and retrieving knowledge helps his protégé in two key ways.

First, it gives Kantarjian a deep understanding of leukemia, and that understanding helps direct his research in fruitful directions. If some study from 1972 suggests an interesting possible follow-up for work that was just published yesterday, Kantarjian knows it, because he remembers the study from 1972.

Second, and more important, Kantarjian’s breadth of knowledge makes him a natural leader of large teams. He knows enough about every specialty to manage specialists, and he knows enough about how different specialties mesh to combine their efforts effectively.

“He isn’t a lab researcher at all,” Freireich said. “He does his research in his head. Then he assembles the proper team for the project and keeps that team running efficiently—all while he’s managing half a dozen other research teams and running his department. It’s an incredible talent, and it makes him more productive than any traditional researcher could ever be.”

Kantarjian gives a different explanation for his success. He says that he owes much of it to the lessons he learned from mentors such as Freireich, Michael J. Keating, MB, BS, and Kenneth B. McCredie, MD.

Chief among those lessons was to ignore tradition, challenge every idea, and dare to seek improvement.

Indeed, Kantarjian said, this is the ethos that permeates MD Anderson and made his career possible.

Tinkering

“Most places expect deference based on seniority or prestige or tradition. Anderson expects the opposite. From the day I arrived, they encouraged me to question the assertions of the most senior people,” said Kantarjian, who expects the same from his youngest researchers. “Even if new ideas prove wrong—and most of them do—they are the only possible path to improvement, so you must keep investigating them. Nothing is ever good enough.”Shortly after his arrival at MD Anderson, a young Kantarjian helped to run some of the first studies that employed interferon against CML. The team discovered, in relatively short order, chemo-interferon regimens that significantly improved upon existing standards of care, but Kantarjian kept on experimenting.

He spent years tinkering with different medications, in different doses, on different schedules—eking out little gain after little gain and waiting for the next big jump.

That jump came years later when Kantarjian helped develop treatment protocols for first-generation kinase inhibitors such as imatinib (Gleevec). The next leap followed a few years after that, when he did the same for second-generation kinase inhibitors that are the current standard of care.

Those clinical studies helped transform CML from a fatal disease to a chronic ailment. CML once killed most victims in 5 years and 80% of them in a decade. Now, as long as patients take their medicines every day, most people can survive it for many years.

Kantarjian’s hunt for new ideas extends far beyond promising new drugs such as imatinib. It extends all the way to previously rejected medications. Decitabine, for example, was first developed in 1964 by researchers who expected big things from its unique activity. It floundered in trials, however, in part because its prolonged myelosuppression made it difficult to determine the preferred dose and schedule. Eventually, concerns about its toxicity led researchers to abandon it.

Kantarjian knew of those studies but decided, in 1992, to try decitabine again with new dosing and schedules. He brought the drug to the United States on an investigator new drug (IND) application and, in collaboration with Jean-Pierre Issa, MD, developed it as an epigenetic low-dose therapy for myeloid diseases.

In 2006, after a phase III trial led by Kantarjian, the FDA approved it for the treatment of myelodysplastic syndrome (MDS). In 2013, after another trial led by Kantarjian, European regulators approved the drug for use in newly diagnosed or secondary acute myeloid leukemia (AML) in older patients who are not candidates for standard induction chemotherapy.

Similarly, clofarabine was “neglected by everyone” when Kantarjian undertook its development as an investigator IND in 1992. He conducted the animal toxicology studies and followed them with phase I, II, and pivotal studies. It took years, but Kantarjian’s trials eventually led the FDA to approve the drug for use in children with ALL who had already failed on two other treatment regimens. Now, there are more than a dozen trials under way that pit the drug—as monotherapy or in combination with other drugs—against a host of cancers.

Kantarjian’s efforts to create the hyper-CVAD regimen show that persistence in action. He first borrowed from the original VAD regimen in myeloma and from the Burkitt pediatric regimen to create a hybrid hyper-CVAD regimen for adult ALL in 1991. He continued to tinker with the regimen, later adding tyrosine kinase inhibitors for the subset of Philadelphia chromosome—positive (Ph+) ALL, and monoclonal antibodies for the subset of pre-B-cell ALL.

Early Upheaval

Today the hyper-CVAD regimen and its derivatives are standard of care in adult ALL, curing more than 50% of patients. Kantarjian hopes that the recent addition of novel monoclonals such as inotuzumab to chemotherapy can further escalate the cure rates to greater than 70%, thus closing the cure gap in adult ALL to approach that for pediatric ALL.Kantarjian’s professional life has been a model of stability. He came to MD Anderson as a fellow in 1981, and he has remained there ever since.

His early years, on the other hand, unfolded amid massive upheaval.

Kantarjian was born in 1954 and raised in Beirut, Lebanon, in a time of peace and prosperity. Beirut was then known as the Paris of the Middle East and widely considered to be one of the most cosmopolitan cities of the world. Things changed abruptly in 1975, just as Kantarjian was completing his bachelor’s degree at American University of Beirut and preparing to begin his medical studies at the same school.

A civil war broke out between Lebanon’s Christians and Muslims and transformed Beirut into a battleground. Roughly 60,000 city residents died during the first two years of the war, which lasted until 1990.

In the midst of all the fighting, Kantarjian continued his medical education.

“During the early years of the war I lost several people I was close to, and I often felt afraid for myself and my loved ones. I coped by doing my best to ignore the things I could not control and focused on living my own life in the best and most productive way possible. For me, that was school,” he recounted.

“I’m sure the experience made me stronger—it made everyone who survived it stronger—but beyond that, I cannot really say what impact it had on me. I don’t think the war really taught me anything except that people need to feel physical safety to thrive.” Kantarjian isn’t sure when he decided to become a physician. He didn’t aspire to the profession in childhood, so he assumes the idea came to him in college. The desire to specialize in leukemia, however, probably dates to meeting Freireich in 1978 when Kantarjian came to MD Anderson for a 4-month elective as a medical student.

Looking Back, Looking Forward

Freireich was then leading the Department of Developmental Therapeutics and was one of the most inspiring cancer researchers in medicine. “He seemed like another bright-eyed kid who wanted to change the world by curing cancer,” Freireich said. “It wasn’t until he came here that we all saw he might have something valuable to contribute. He had incredible purpose and discipline for one so young. When he first got here, for example, he had a habit of being slightly late to meetings, and I called him on it. He hasn’t been late to a meeting in three decades,” Freireich said.Looking back at his life, Kantarjian sees both a lot of hard work and a lot of luck.

“Being a leukemia specialist over the past few decades has been the most satisfying job imaginable because of the incredible strides we’ve made in treating patients, but there’s no way I could have predicted those improvements when I chose to specialize.

“I could have just as easily stumbled into some field where there was no money for research or one where the research just hit dead end after dead end and patients kept dying a few weeks after diagnosis….As things are, I’m smiling when I walk into work each morning and smiling when I walk back out.”

When Kantarjian’s workday does end, usually about 12 hours after it begins, he relaxes by painting in the styles of his favorite artists, Matisse and Cézanne, or by reading authors like Salman Rushdie, Philip Roth, and Graham Greene, or by jogging through Houston’s parks.

He has also stayed very close to his family. Indeed, both of his parents and four of his siblings eventually followed him from Beirut to Houston. His parents have passed away, but he gets together with his brothers and sisters at least once a week.

“My wife says we meet way too much,” said Kantarjian, whose 30-year-old son also lives in town. “But that’s the culture I come from. We value family, particularly those of us who felt ourselves in danger of losing that family.”

Looking forward, Kantarjian plans to focus his efforts in several areas.

He is particularly excited about the potential of using monoclonal antibodies to treat ALL. The addition of rituximab to combination chemotherapy has already produced encouraging results, and newer medications also seem promising. For example, the anti-CD22 antibody inotuzumab ozogamicin has produced significant single-agent responses in relapsed and refractory ALL.

He is also excited about improved epigenetic therapies with better hypomethylating agents (SGI110) and immune-oncology strategies in AML and MDS.

In addition to his research, Kantarjian plans to continue writing and speaking about issues such as chemotherapy drug shortages, the high cost of cancer drugs and cancer care, and broad health insurance coverage of patients with cancer.

A Visionary Leader, Passionate About Patient Care

Emil J. Freireich, MD

Ruth Harriet Ainsworth Chair

Developmental Therapeutics

The University of Texas MD Anderson Cancer Center

Houston, TX

Hagop M. Kantarjian, MD, “has a photographic, encyclopedic memory unlike any other I’ve ever encountered. He can absorb huge quantities of information and remember it all forever.”

“He isn’t a lab researcher at all. He does his research in his head. Then he assembles the proper team for the project and keeps that team running efficiently —all while he’s managing half a dozen other research teams and running his department. It’s an incredible talent, and it makes him more productive than any traditional researcher could ever be.”

Elias Jabbour, MD

Associate Professor

Department of Leukemia

The University of Texas MD Anderson Cancer Center

Houston, TX

“I want to highlight two things: his incredible impact as a mentor on so many clinicians in the field of leukemia and his research. “He has mentored so many of us and many of us have gone on to become leaders in the leukemia field around the world. His mentees have established leading leukemia programs and have gone on to conduct leading leukemia research, which is immense. “In the United States, his visionary research has led to many drug approvals by the FDA in the field of acute lymphoid leukemia, chronic myeloid leukemia, and myelodysplastic syndrome.

“Hagop has done more than just conduct clinical research. He brought clinical research to the patient and impacted the lives of human beings. This is an amazing achievement. “Hagop is also passionate and concerned about the financial burden of cancer on patients. In the US, many people cannot afford cancer drugs without going into bankruptcy, but Hagop has taken up the cause to write, speak, and promote the importance of providing care and value to patients. Regardless of politics, this is a huge issue that Hagop has undertaken. “In summary, Hagop’s vision is not focused on the next 6 months or year. It’s more than just being a chairman of a department. No, he thinks about how the research he’s conducting might affect patient lives in 10 or 15 years and that makes him a visionary leader.”

DR KANTARJIAN’S SELECTED PAPERS

• Topp MS, Gökbudget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study [published online December 15, 2014]. Lancet Oncol. pii: S1470-2045(14)71170-2. doi: 10.1016/S1470-2045(14)71170-2.
• Kadia TM, Kantarjian HM, Thomas DA, et al. Phase II study of methotrexate, vincristine, pegylated-asparaginase, and dexamethasone (MOpAD) in patients with relapsed/refractory acute lymphoblastic leukemia [published online November 4, 2014]. Am J Hematol. doi: 10.1002/ajh.23886.
• Falchi L, Kantarjian HM, Wang X, et al. Significance of deeper molecular responses in patients with chronic myeloid leukemia in early chronic phase treated with tyrosine kinase inhibitors [published online September 12, 2013]. Am J Hematol. 2013;88(12):1024-1029.
• Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367(22):2075-2088.
• Badoux XC, Keating MJ, Wang X, et al. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL [published online January 18, 2011]. Blood. 2011;117(11):3016-3024.
• Quintás-Cardama A, Ravandi F, Liu-Dumlao T, et al. Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia [published online October 15, 2012]. Blood. 2012;120(24):4840-4845.
• Kantarjian HM, Giles FJ, Bhalla KN, et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase following imatinib resistance or intolerance: 24-month follow-up results [published online November 22, 2010]. Blood. 2011;117(4):1141-1145.
• Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363(12):1117-1127.
• Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia [published online June 5, 2010]. N Engl J Med. 2010;362(24):2260-2270.
• Walter RB, Kantarjian HM, Huang X, et al. Effect of complete remission and responses less than complete remission on survival in acute myeloid leukemia: a combined Eastern Cooperative Oncology Group, Southwest Oncology Group, and M.D. Anderson Cancer Center Study [published online February 16, 2010]. J Clin Oncol. 2010;28(10):1766-1771.
• Kantarjian HM, Cortes J, La Rosée P, Hochhaus A. Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase. Cancer. 2010;116(6):1419-1430.
• Quintás-Cardama A, Kantarjian H, Manshouri T, et al. Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera [published online October 13, 2009]. J Clin Oncol. 2009;27(32):5418-5424.