From Death Sentence to Manageable Condition
A story about the National Institutes of Health and a rare leukemia
In the annals of medical breakthroughs, few stories are as compelling as that of imatinib (Gleevec/Glivec) and its impact on chronic myeloid leukemia (CML). This narrative encompasses not only a remarkable scientific achievement but also a profound human triumph; the story of transforming a once-fatal diagnosis into a manageable chronic condition and fundamentally changing how we approach cancer treatment. At the heart of this revolution lies a tale of scientific curiosity, persistent research, public-private collaboration, and the critical role played by the National Institutes of Health (NIH).
In light of the recent attacks on the NIH and America’s most critical health research organizations by individuals who wish them harm, I wanted highlight the story of imatinib and how the NIH directly produced, in partnership with commercial pharmaceutical companies, one of many life saving drugs.
My family has been the beneficiary of the NIH’s dedication to funding research on the medical conditions that afflict Americans—even ones that affect a small number of people like chronic myeloid leukemia. Around the year 2009, my mom was diagnosed with CML at the age of 40. She was able to continue living a normal life as a fifth grade teacher for eight years thanks to the groundbreaking work described in this article and the subsequent drug development that occurred. She passed away in 2017 at the age of 48 from CML after the cancer mutated in such a way that the class of drugs started by imatinib were no longer effective.
Eight years of relatively normal life for a patient diagnosed with CML was not possible prior to the research that produced imatinib. My mom’s story is an outlier. Many patients with CML on imatinib or a similar tyrosine kinase inhibitor can live decades without the same mutational resistance occurring.
If you are unaware of how the NIH affects your life, I hope this story encourages you to learn more. The indiscriminate attacks on the NIH and the research it funds are attacks on you and future American families who serve to benefit.
NIH funding is not fraud, waste, or abuse.
Understanding Chronic Myeloid Leukemia
Chronic myeloid leukemia is a rare form of blood cancer that begins in the bone marrow with the abnormal production of white blood cells. Before the turn of the millennium, a CML diagnosis often meant a grim prognosis, with patients facing a difficult journey through invasive treatments, bone marrow transplants, and ultimately, for many, an early death.
The disease typically progresses through three phases: chronic, accelerated, and blast crisis. In the chronic phase, patients might experience fatigue, weight loss, night sweats, and an enlarged spleen, though some remain asymptomatic. As the disease advances to accelerated and blast crisis phases, symptoms intensify dramatically, with increasing infections, bleeding, and bone pain. Prior to modern treatments, the median survival after diagnosis was approximately 3-5 years, with the disease inevitably progressing to its fatal blast crisis phase.
My mom reached the blast crisis phase in February 2017 after seven years of well-controlled disease in the chronic phase. By July of the same year when she passed away, she had been in and out of the hospital, faced chemotherapy, lost her vision, and endured persistent infection.
The traditional treatments available before the imatinib era were limited and often debilitating. Interferon alpha therapy, while sometimes effective, caused severe flu-like symptoms, depression, and other significant side effects that dramatically reduced quality of life. Bone marrow transplantation offered the only potential cure but came with substantial risks and was not viable for many patients due to age or lack of suitable donors. Conventional chemotherapy provided temporary relief but could not halt the disease's progression.
The Philadelphia Chromosome: A Critical Discovery
The story of modern CML treatment begins in 1960 with a fundamental discovery supported by NIH funding. Researchers Peter Nowell and David Hungerford identified a distinctive chromosomal abnormality in CML patients while working in Philadelphia. This abnormality, subsequently named the "Philadelphia chromosome," represented the first consistent chromosomal abnormality linked to any cancer, opening the door to understanding cancer at the genetic level.
The NIH's commitment to basic science research proved crucial in the decades that followed. Through sustained NIH grant support, researchers Janet Rowley, Herbert Abelson, and others determined in the 1970s and 1980s that the Philadelphia chromosome resulted from a reciprocal translocation between chromosomes 9 and 22. This translocation creates the BCR-ABL fusion gene, which produces an aberrant tyrosine kinase protein that drives the uncontrolled cell growth characteristic of CML. This protein, would eventually be targeted by a new class of drugs—the tyrosine kinase inhibitor.
These NIH-funded basic science discoveries were revolutionary, transforming our understanding of cancer from a mysterious affliction to a disease with specific molecular drivers. For the first time, scientists could envision targeting the precise molecular abnormality causing a cancer, rather than broadly attacking all rapidly dividing cells as conventional chemotherapy does.
Developing a Targeted Therapy
The path from understanding the molecular basis of CML to developing an effective treatment spanned many years and exemplifies successful public-private partnership in medical research. By the late 1980s, researchers at Ciba-Geigy (later Novartis) began screening compounds that could inhibit protein kinases.
Dr. Nicholas Lydon at Ciba-Geigy collaborated with Dr. Brian Druker, whose research was supported by NIH grants, to identify compounds that could specifically inhibit the BCR-ABL tyrosine kinase. In 1992, they discovered a promising compound that would eventually become imatinib. This molecule was designed to fit precisely into the ATP-binding site of the BCR-ABL protein, preventing it from activating and blocking the signals that drive leukemic cell growth.
The NIH's role extended beyond funding basic research. When initial laboratory tests showed the compound could kill CML cells while leaving normal cells relatively unharmed, the pharmaceutical company hesitated to develop the drug fully due to the relatively small market for CML treatments—approximately 5,000 new cases annually in the United States. When the market is small, commercial drug companies can be unlikely to fund early, high risk research. Here, the NIH stepped in again, with the National Cancer Institute (NCI) advocating for the development of this promising therapy despite market concerns and helping secure orphan drug designation to provide financial incentives for continued development.
The Clinical Trials: A New Hope
The journey from laboratory to clinic began in earnest in 1998 when Phase I clinical trials of imatinib (then known as STI571) commenced with 31 patients who had failed interferon therapy. The NIH played a pivotal role in supporting these trials through both funding and coordination across multiple research centers.
The results were nothing short of miraculous. In a disease where responses to existing treatments were modest at best, 98% of patients achieved complete hematologic response (normalization of blood counts). Patients who had been bedridden returned to normal activities within weeks. The early trial results were so impressive that researchers initially questioned whether they could be real.
Phase II trials, partially coordinated through NIH-funded cancer centers, showed similarly dramatic results, with high response rates and minimal side effects compared to existing treatments. The contrast with previous therapies was stark: instead of causing systemic toxicity, imatinib precisely targeted the cancer cells' unique vulnerability.
Transformation in Treatment and Quality of Life
The FDA approved imatinib in May 2001 after one of the fastest review processes in its history—less than three months. This unprecedented speed reflected both the compelling efficacy data and the desperate need for better CML treatments.
The impact on survival rates was profound. Prior to imatinib, the five-year survival rate for CML was approximately 30%. After imatinib's introduction, this figure skyrocketed to over 83%, approaching the life expectancy of the general population for patients who respond well to treatment. A disease that once inevitably progressed to a fatal outcome became, for most patients, a manageable chronic condition.
Perhaps even more remarkable than the survival statistics was the transformation in patients' quality of life. Before imatinib, CML treatments like interferon alpha caused debilitating side effects that often forced patients to choose between extending their lives and maintaining their quality of life. Many became too ill to work, spend time with family, or engage in everyday activities.
Imatinib changed this paradigm completely. Most patients on imatinib experience only mild to moderate side effects. While not trivial, these side effects are dramatically less severe than those associated with previous treatments and are often manageable with supportive care.
The stories from patients themselves tell the most compelling narrative. People who had prepared for death returned to work, resumed hobbies, watched their children grow up, and experienced milestones they had never expected to see.
Here is a great link to a patient story.
This improvement in quality of life represented a fundamental shift in cancer treatment philosophy. For the first time, a cancer therapy was not just extending survival at any cost but allowing patients to maintain meaningful, productive lives during treatment. The NIH recognized this paradigm shift and invested in quality-of-life research to document these benefits formally, providing evidence that would influence future drug development priorities. While hard science gets to the cures, “soft science” on quality of life and other topics are critical to understand the impact of treatments on patients.
Addressing Resistance and Moving Forward
Despite imatinib's remarkable success, challenges remained. Approximately 20-30% of patients develop resistance to imatinib over time, primarily due to mutations in the BCR-ABL gene that prevent the drug from binding effectively. The NIH continued funding research to understand and overcome these resistance mechanisms.
This ongoing research, supported by NIH grants, led to the development of second-generation tyrosine kinase inhibitors like dasatinib and nilotinib, approved in 2006 and 2007, respectively. These drugs can overcome some forms of resistance to imatinib and provide additional options for patients.
The NIH's commitment to translational research—bridging laboratory discoveries and clinical applications—proved vital in these advances. The NCI's Experimental Therapeutics Program (NExT) and similar initiatives helped accelerate the development of these next-generation treatments.
The Human Impact: Beyond Statistics
While survival statistics and scientific breakthroughs tell part of the story, the human impact of imatinib extends far beyond numbers. Patients diagnosed with CML today face a fundamentally different reality than those diagnosed just 25 years ago.
Modern CML patients typically take a once-daily pill with manageable side effects. Most continue working, caring for their families, and pursuing their passions. Regular monitoring ensures the treatment remains effective, but for many, CML becomes a background concern rather than a life-defining struggle.
This transformation reflects the ultimate goal of medical research: not just extending life but preserving its quality and meaning. The NIH's commitment to patient-centered outcomes research has helped document these benefits and ensure they remain central considerations in drug development.
Conclusion
The story of chronic myeloid leukemia and imatinib stands as a testament to what biomedical research can achieve when basic scientific curiosity receives sustained support. From the initial discovery of the Philadelphia chromosome to the development of targeted therapies, each step in this journey depended on the persistence of researchers and the steadfast support of institutions like the National Institutes of Health.
This narrative also demonstrates the power of collaboration between public institutions and private industry. The NIH funded the basic science that identified the target, supported the early development work, helped coordinate clinical trials, and ensured the therapy reached patients despite market hesitations. The pharmaceutical industry provided the medicinal chemistry expertise, clinical trial infrastructure, and manufacturing capabilities necessary to bring the drug to market.
For thousands of CML patients who have received the gift of extended life with preserved quality, this scientific success story is profoundly personal—a revolution measured not just in clinical trial data but in birthdays celebrated, graduations attended, and lives fully lived.
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