By Alison Wakoff Loren, MD, MS and Mikkael A. Sekeres, MD, MS
We leukemia doctors live in exciting times, we tell one another.
In an unprecedented year, the FDA has now approved six drugs for the treatment of acute leukemias, the rare, but grim, blood cancers that have been treated essentially with the same poisons since the 1970’s. Some of the new drugs are for patients whose leukemia has proven stubbornly recalcitrant to other therapies, and have a life expectancy measured in months. None of these drugs is curative, though.
As a result, our patients are placed in the unenviable position of deciding between technologically sexy, toxic, variably effective, and costly treatments; palliative care; or hospice. And we, their doctors, enticed by the allure of shiny new tools in our medicinal toolbox, risk justifying the stereotype of oncologists eager to administer chemotherapies to our dying patients during their final days, at the expense of their quality of life and time with family.
Within the past few weeks alone, the FDA approved two of these drugs: Mylotarg, a monoclonal antibody with a checkered past, as it was okayed by the FDA under its accelerated approval mechanism in 2001; withdrawn from the market in 2012, when follow up studies failed to confirm its efficacy; and now re-approved with an expanded label for adults and children with acute myeloid leukemia (AML); and Kymriah, or CAR T-cells, the first-ever approval for a gene therapy. This “living drug” benefits patients with acute lymphoblastic leukemia, using a technique that genetically modifies a patient’s own immune cells, redirecting them to fight their cancerous blood cells and unleashing their fury with astounding results: over 80% of children and young adults achieve a remission of their cancers.
But as the superhero Spider Man knew all too well, with great power comes great responsibility. Particularly with CAR T-cells, the side effects to treatment can be substantial. Many children require a stay in the intensive care unit, without guarantee of a clinically meaningful benefit. While most achieve a remission, approximately half will also relapse within one year of receiving therapy. Almost one-quarter of patients who sign on to CAR T-cell therapy never get treated, either because of manufacturing issues, or because their disease marches on too rapidly. And the therapy is breathtakingly expensive: $475,000 for Kymriah itself, not including costs for hospitalization, other drugs with newly expanded labels to manage the side effects, or for a subsequent bone marrow transplant, which may be necessary to actually cure the leukemia.
One of our patients is a petite, whip-smart woman who had already survived treatment for high risk breast cancer, which included a bone marrow transplant, before developing AML. After two grueling courses of chemotherapy, she underwent another bone marrow transplant from which she had serious side effects requiring multiple hospitalizations. Her leukemia went into remission, she recovered, and enjoyed a terrific two years in which she was able to travel, participate in community activities, and spend time with friends and family. About 3 months ago, though, her leukemia returned, but this time was refractory to two more rounds of chemotherapy. It was time for a tough conversation.
We talked about all the treatment and side effects she had endured. We discussed other treatments: more potent chemotherapy, clinical trials, supportive care. We reflected on her spirit and her values. As her time was assuredly limited, she decided, together with her family, to seek hospice care and to spend her remaining time surrounded by her loved ones at home, focused on dignity and comfort. Nurses and social workers were mobilized, equipment was delivered to her home, and her family gathered to be with her.
But then, the very next day, the FDA approved a drug that treats the exact subtype of AML that she has, one that doesn't work more often than it does, and one that has not been shown to improve a person’s survival. In one of the more Orwellian aspects of our health care system, patients receiving “active therapy,” such as this drug, cannot remain on hospice.
We both know this scenario well, and have faced this conundrum with both elation and exasperation. As oncologists, we have “done the right thing” – the good, hard work of having honest conversations about dying. We have breathed a collective sigh of relief, with our patients and their families, at the tranquil end of their harrowing battles with cancer, at the sad joy and unsettled peace that comes with a decision to accept death as inevitable, while celebrating their lives and treasuring their remaining moments. A conversation about the new drug would reopen these wounds, throw our patients and their families into turmoil, and ultimately to what end? Perhaps to buy some time, but without a cure.
This predicament is a sign of the times, and presents an almost impossible dilemma to our patients and to us. We try to be good doctors: we recognize the value of honest conversations and focus on quality of life. We seek to avoid risky interventions in patients who will not benefit from them. We try to practice more humanely in an era of exponential technologic and biologic progress.
But how do we encourage and value conversations, introspection and connection while simultaneously incorporating the incredible advances we have at our fingertips? When patients expect a deus ex machina – and it is increasingly likely that they will get one – it is challenging to focus our conversations on what is most essential: relationships, comfort, and dignity.
One of us called this patient a few days later and offered her the drug. The next day she decided to proceed. It’s been about two weeks now and she says she feels “scary good.” That may be the best way to describe the future of cancer therapy.
Alison Wakoff Loren, MD, MS, is Associate Professor of Medicine, Hematology/Oncology; Vice Chair, Faculty Development, Department of Medicine, Perelman School of Medicine at University of Pennsylvania.
Mikkael Sekeres, MD, MS, is Professor of Medicine and Director of the Leukemia Program at Cleveland Clinic, and former Chair, Oncologic Drugs Advisory Committee, FDA.