In the 1950s, a diagnosis of pediatric acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) was a death sentence. In the 2020s, five-year overall survival of children with ALL and AML with modern therapy now exceeds 90 percent and 60 to 70 percent, respectively.1–4 Clinical trials conducted by the Children's Oncology Group (COG) and other pediatric oncology consortia have achieved these major accomplishments via risk-adapted multi-agent chemotherapy regimens, effective and safe treatment of the central nervous system (CNS), refinement in risk stratification using leukemia-associated genetics and early measurable residual disease assessment, incorporation of relevant targeted therapies for some patients, and improvement in supportive care.2,5 Yet chemotherapy drug shortages – an increasing occurrence in recent years – endanger this remarkable progress in pediatric oncology. In short, lack of access to vital chemotherapy drug supply is literally killing our patients.
A recent survey of medical oncologists reported that 83 percent of physicians were unable to prescribe their preferred chemotherapy agent(s) in the prior six months. Drug unavailability necessitated a major change in treatment for their patients.6 Similarly, surveys of pediatric oncologists showed that 66 percent reported drug shortages that significantly hindered patient care.7,8 Within the past decade, eight of the 10 major chemotherapy agents used to treat childhood ALL have been on shortage and unavailable for clinical use.9 Furthermore, oncologists have also experienced intermittent lack of access to critical supportive care medications (e.g., anti-emetics, leucovorin, intravenous immunoglobulin), anti-infectious agents, blood pressure support medications, electrolyte supplementation, and even normal saline for fluid resuscitation, all of which negatively impact the ability to deliver high-quality curative anti-cancer therapy. Such drug shortages have led to delayed clinical trials,10,11 increased patient morbidity,12 substitution or omission of critical medications resulting in increased rates of relapse13 and toxicity,14 increased cost and resource utilization to manage drug shortages,10,15 and ethical supply-versus-demand dilemmas for physicians regarding allocation of limited chemotherapy resources among their patients.9,16
Vincristine, a vinca alkaloid approved in 1963 by the U.S. Food and Drug Administration (FDA) for patients with cancer, is one of the oldest chemotherapies still in use. It is an essential component of treatment for nearly every type of childhood cancer, including acute leukemia, Hodgkin and non-Hodgkin lymphoma, CNS tumors, hepatoblastoma, neuroblastoma, sarcoma, and Wilms tumor. No therapeutic equivalent exists for vincristine. Due to its crucial role in cancer therapy and relatively inexpensive cost, vincristine is currently one of 18 chemotherapy drugs on the World Health Organization's list of essential medications.17 In 2019, Teva Pharmaceuticals made the economic decision to discontinue its vincristine production, leaving Pfizer as the drug's sole commercial supplier and resulting in widespread shortages that profoundly affected life-saving therapy for tens of thousands of children with cancer in the United States and worldwide. The vincristine example highlights the disproportionate risk of drug shortages in older generic injectable drugs that are difficult to manufacture, have low profit margins, and are often manufactured by a single company. These essential factors further limit the ability to increase scalable production capacity quickly in the setting of manufacturing problems or increased clinical demand.9
Asparaginase is another critical component of childhood ALL therapy that has markedly improved patients' survival since its intercalation into chemotherapy regimens in the 1960s.18,19 Modern ALL therapy includes longer-lasting pegylated asparaginase from Escherichia coli, which is associated with various toxicities (e.g., allergic reaction, thrombosis, pancreatitis, hepatoxicity, silent inactivation) requiring medication discontinuation in 12 to 25 percent of patients. Asparaginase discontinuation without delivery of all protocol-prescribed dosing is clearly associated with increased relapse risk and inferior disease-free survival in children with ALL.20,21 Substitution with Erwinia chrysanthemi asparaginase (Jazz Pharmaceuticals), an alternative shorter-acting formulation of asparaginase, has demonstrated non-inferiority and was FDA-approved for patients with pegylated asparaginase hypersensitivity in 2011.22 However, Erwinia asparaginase has been intermittently unavailable due to drug supply issues, which has resulted in recurrent global shortages of this essential medication. Similarly, nelarabine (Novartis), a purine nucleoside analog critical for successful treatment of patients with T-cell ALL (T-ALL), has been in severe shortage since 2018. The COG trial AALL0434 (NCT00408005) recently demonstrated markedly improved disease-free survival and reduction in CNS relapse with addition of nelarabine to intensive post-induction therapy in children and adolescents/young adults with T-ALL,23 and intermittent lack of access to nelarabine has created tremendous stress within the pediatric oncology community.
During the past decade, many other essential chemotherapy drugs critical to the care of children with cancer have been in shortage, including azacytidine, bleomycin, cisplatin, cytarabine daunorubicin, doxorubicin, etoposide, fludarabine, methotrexate, and thiotepa. In recent years, medication shortages have occurred more frequently and have lasted longer, placing cancer patients at significant risk of suboptimal therapy and ensuing inferior clinical outcomes. In response to this challenge, a Working Group on Chemotherapy Drug Shortages in Pediatric Oncology was established in 2013. This expert panel of hematologists/oncologists and bioethicists developed consensus statements on core ethical values and practical actions for managing and preventing drug shortages in pediatric oncology.9 These recommendations will be most effective when met with definitive action and cooperative engagement from the FDA, pharmaceutical industry, health care systems, professional organizations, clinical trial consortia, and patient advocates. A critical next step is greater involvement by federal, state, and local governments to recognize chemotherapy drug shortages as an international emergency and to hold pharmaceutical companies accountable, potentially via providing subsidies to maintain uninterrupted chemotherapy drug supply, incentivizing production and high-quality manufacturing practices, and ensuring equitable reimbursement practices.17
We live in a dichotomous world that allows economics to drive shortages in life-saving, decades-old, and often-inexpensive medications that have no therapeutic equivalents for substitution and are critical to upfront cancer therapy, while also spending tens of billions of dollars on novel immunotherapies (e.g., antibody-drug conjugates, bispecific antibodies, chimeric antigen receptor T cells) to treat patients with relapsed disease. It is ironic that the United States, with its unparalleled economic and biomedical capabilities, has also become a leader in drug shortages, making it increasingly difficult for patients living in our medically premier, resource-rich country to receive the life-saving cancer treatments that they need and deserve. Altering treatment plans and withholding critical chemotherapeutic agents due to medication shortages threatens our ability to maintain or improve current cure rates. Until we recognize and proactively address ongoing chemotherapy drug shortages, children (and adults) with cancer will continue to suffer unnecessarily the potentially devastating consequences of this major public health crisis.
Dr. Pommert indicated no relevant conflicts of interest. Dr. Tasian receives/d research funding from Incyte Corporation and Gilead Sciences and serves on the scientific advisory boards for Aleta Biotherapeutics and Kura Oncology.