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Without Genomic Sequencing, I Would Not Be Alive Today

Understanding ALL on a granular level will mean more patients will survive this difficult-to-cure leukemia.


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Lukas Wartman, MD

Lukas Wartman, MD

The extreme fatigue I experienced during the winter of my fourth year in medical school, in 2003, was easily attributable to the rigors of my medical training and the lack of sleep that comes from trying to keep up with an intensely busy schedule. I was looking forward to resting and recuperating during an upcoming month-long break. But instead of feeling better, the fatigue became increasingly worse, and other worrisome symptoms developed, including bone pain, especially in my legs, drenching night sweats, and chronic low-grade fevers. 

I instinctively knew something was wrong, but I minimized the problem. I told myself that I probably had mononucleosis or another viral infection. I just needed a bit more time to rest and let my body heal on its own. During the break, I went home to Chicago to stay with my parents, sure that my symptoms would soon improve, but they continued to worsen.

Finally, a blood test showed that I was pancytopenic, and an oncologist I saw recommended a bone marrow biopsy. As a professional courtesy, before telling me the diagnosis, he had me look at the slides of my bone marrow aspiration, and I could see it was full of leukemia cells. 

I was 25 and completely unprepared for the subsequent diagnosis of acute lymphoblastic leukemia (ALL), which is more common (and more easily curable) in children than adults—cure rates for children now approach 90%. For adults like me, the path to a positive outcome was more tenuous. Still, my odds for a cure were relatively good—better than the approximately 40% average cure rate for adults with my cancer—because of my otherwise good health, young age, and the fact that I didn’t have any known unfavorable prognostic risk factors.

Understanding the Genetic Abnormalities of Cancer 

Because there were no clinical studies open for adult patients with ALL at the time of my diagnosis, I was treated with a chemotherapy induction regimen based on results from the Cancer and Leukemia Group B (CALGB) 8811 study, which included cyclophosphamide, daunorubicin, vincristine, prednisone, and asparaginase (Elspar),1 which put me in a durable remission for 5 years. I thought I was cured, and my medical education and career continued to progress during that time. 

However, in 2008, I relapsed. Now, my chances for a cure were dramatically reduced, and my treatment option was clear: an allogeneic bone marrow transplant with a myeloablative conditioning regimen. My younger brother, who is a human leukocyte antigen–matched sibling, was my donor.

Although the transplant had significant toxicity, within a year I was healthy enough to return to work and complete my clinical rotations as an oncology fellow. I then joined the laboratory of Timothy J. Ley, MD, in the Division of Oncology and the McDonnell Genome Institute at Washington University School of Medicine in St. Louis, which was investigating the key principles of acute myeloid leukemia (AML), to start my postdoctoral work. 

Genetics and cancer had fascinated me since my days as an undergraduate, and joining Dr. Ley’s laboratory was a natural fit for me. Moreover, it gave me a chance to study a cancer different from my own. When I joined the lab, Dr. Ley and our colleagues were just reporting the sequencing results of the first cancer genome—a case of AML—the results of which would turn out to be beneficial for me after my second relapse in 2011. 

By then, Dr. Ley had launched a research protocol for the genomic sequencing of patients with lymphoid malignancies, including ALL, and he invited me to join the study. When I was asked to enroll in the clinical study, I wasn’t thinking about genomic sequencing as a therapeutic diagnostic test, but rather as a way to understand the underlying genetic abnormalities of the disease and what made ALL so much deadlier in adult patients than in children. I was not expecting the results to be clinically important for me, but, in fact, the sequencing results saved my life, and that’s not an exaggeration.

Overcoming the Odds

Learning that I had relapsed for the second time was beyond disappointing. I knew that most oncologists consider a second relapse in adult ALL to be incurable and most often fatal—even after a first relapse, overall survival odds plummet to between 5% and 10%. Still, I was optimistic that a second allogeneic transplant would be successful. 

As an ALL survivor, I am in a good position to counsel patients struggling with their ALL diagnosis or with the rigors of their treatment.
— Lukas Wartman, MD

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The salvage chemotherapy I received was so harsh, I nearly died from treatment complications, and it was not effective. I did not enter into a remission. Now, my only hope for a chance at survival appeared to be identifying a novel target from my sequencing results and a magic bullet therapy to hit the leukemia, but I knew the odds at being successful were very low. Indeed, the whole-genome sequencing and exome sequencing results did not identify any candidate targets for therapy. 

Finally, the RNA sequencing data showed that my leukemia cells had high wild-type FLT3 overexpression. While it was good news that the sequencing results had uncovered a novel, unexpected target in ALL, it was still unclear whether my leukemia would respond to an inhibitor of FLT3. 

With no other options at hand, I started taking the receptor tyrosine kinase inhibitor sunitinib (Sutent), which was approved by the U.S. Food and Drug Administration (FDA) for the treatment of other cancers but known to inhibit FLT3. It had what I can only describe as a miraculous effect. Two weeks after taking the drug, I was in a complete remission and underwent a second allogeneic transplant from an unrelated matched donor. I’ve been in remission ever since.

Making Career and Life Adjustments

Fifteen years after my initial diagnosis of ALL, I’m still living with the aftereffects of the cancer and its treatments. I continue to have significant, ongoing complications from graft-vs-host-disease, affecting the skin, eyes, mouth, and joints. The high amounts of corticosteroids that I have had to take to treat graft-vs-host disease led to avascular necrosis in my left hip, necessitating a hip replacement in the past year. Lingering fatigue has limited my productivity at times and my ability to work as hard as I’d like. On the flip side, my cancer experience has given me a greater appreciation for striking a better work/life balance, and I’m learning to pace myself and not take life for granted.

Despite my health issues, cancer hasn’t changed the trajectory of my clinical and research career. I have always been interested in the biology of leukemia, and even before my ALL diagnosis, I was interested in treating patients with all types of leukemia. As an ALL survivor, I am in a good position to counsel patients struggling with their ALL diagnosis or with the rigors of their treatment, especially in the relapsed setting. I hope that I am making a difference in how my patients cope with their leukemia. ALL is becoming an important part of my laboratory research as well.

Curing More Patients in the Future

I recognize how fortunate I am to be alive and how difficult a task it was to (potentially) cure my ALL. I wanted to share my story not because of my good luck, but because it illustrates how cancer genomics and precision medicine can be clinically relevant. It is unfortunate that the option is not possible for all patients at the present time, but that doesn’t diminish the potential benefits that can be derived from trying to understand cancer at a granular level with the hope of curing many more patients in the future. 

Although it’s true that we have to temper our enthusiasm for precision medicine with the reality that we are not currently able to find actionable targets for most patients, I am living proof that precision medicine can be life-saving for some patients. There is still a great deal of work to do, and I hope we will continue to support research that employs sequencing, especially clinical research that is tied to unraveling whether there are genetic signatures associated with treatment response in specific patients.

I would love to think that we will be able to come up with effective, relatively nontoxic drugs like imatinib—which is used primarily for the treatment of chronic myeloid leukemia—to treat many more types of cancers, but that’s not the reality right now. Nevertheless, we are making progress. Many useful targets have been identified that have led to successful drug therapy. Acute myeloid leukemia is a great example of what has been accomplished through precision medicine, with the FDA’s approval of both an IDH1 and an IDH2 inhibitor to treat patients with those respective mutations.

We are succeeding at chipping away at cancer using different sequencing approaches. And I remain convinced that in the future, more patients will be cured of their cancer, as we will be better at targeting tumor-specific genetic/genomic alterations with matched therapies. ■

Dr. Wartman is Assistant Professor in the Section of Cell Biology, Division of Oncology, at Washington University Medical School and Assistant Director, Section of Cancer Genomics, at the McDonnell Genome Institute at Washington University in St. Louis.

REFERENCE

1. Larson RA, Dodge RK, Burns CP, et al: A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood 85:2025-2037, 1995.


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