Acute lymphoblastic leukemia (ALL) is a rare hematologic malignancy that shows bimodal incidence, with most cases occurring in children (80%), followed by a gradual increase in incidence after 50 years of age [1, 2]. Approximately three-quarters of adult ALL cases are of B cell lineage, the majority originating from B lymphocyte precursors (BCP-ALL) [3].
For most adults with ALL, front-line chemotherapy will result in hematologic complete remission (CR) (based on morphologic assessment), which is a prerequisite, but by itself not sufficient, for cure. Patients who achieve hematologic CR can potentially harbor leukemic cells in the bone marrow. The presence of leukemic cells that are below the threshold of detection by conventional morphologic methods is referred to as minimal residual disease (MRD).
Large-scale analyses have shown a strong association between the presence of MRD after front-line chemotherapy and poor long-term outcomes, including increased risk of relapse and shorter relapse-free and disease-free survival [4,5,6,7,8]. European clinical guidelines therefore recommend testing patients in first hematologic complete remission (CR1) for MRD for the purpose of risk stratification [9], and this is reflected in national protocols for the treatment of adult ALL. This risk stratification dictates whether immediate (allogeneic) hematopoietic stem cell transplant (HSCT) is indicated for a given patient, because of a higher risk of relapse, or whether that patient should receive additional chemotherapy, because the lower risk of relapse would outweigh the mortality and morbidity associated with HSCT. Nevertheless, the current European guidelines lack deep clarity on the most appropriate use of MRD status and other prognostic factors for clinical decision-making in adults. In addition, the designated MRD status of an individual patient may be influenced by the detection technology and the time point of measurement. Decisions about treatment are further complicated by the recent approvals of immunotherapies for the treatment of adults with ALL (including blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor T cell therapy), as it is not yet clear how HSCT should be used in future treatment pathways incorporating these agents.
The concept of cure has been highlighted as particularly important when assessing the value of immunotherapies, for which treatment outcomes suggest that cure may be an increasingly achievable goal [10,11,12]. The long-term survival of patients who have received a new treatment versus the standard of care (SOC) is frequently critical to quantify potential clinical and economic benefits; however, data over longer time frames are rarely available, necessitating estimation of long-term outcomes using assumptions informed by expert opinion. Specifically, this includes understanding after what time point it may be assumed that patients will continue to survive in the long term, and what will be their long-term health status. This study was initiated to provide such estimates for patients in first hematologic CR in a transparent and methodologically sound manner, in the absence of previously published findings for this patient population.
Given the demonstrable prognostic implications of MRD in patients with BCP-ALL, this study aimed to use MRD status as the basis to explore concepts of cure, with the focus on adults with Philadelphia chromosome-negative (Ph−) BCP-ALL. Patients with Ph+ BCP-ALL were not considered in this study, as this group represents a minority with its own specific treatment pathways (including the use of tyrosine kinase inhibitors) and a distinctly different prognosis. This study also aimed to understand clinicians’ perspectives on the relationship between HSCT and cure, specifically whether HSCT is required for a patient to be considered “cured” in current clinical practice. Further, the study aimed to elicit estimates of the proportion of patients who meet specialists’ own definitions of cure in current clinical practice, and to garner understanding of the long-term prognoses of these patients (in terms of mortality and health-related quality of life, HRQL).
Several of these questions were deemed to be best answered through exploration of expert opinion from clinicians currently treating patients with ALL. Therefore, a consensus approach widely applied in health service research—Delphi methodology—was used for this study.
Representatives from five countries were included in this study: France, Germany, Italy, the UK, and Australia. It was considered valuable to gather country-specific insights into these various concepts, particularly given the differences between national protocols for adult ALL and differences in actual clinical practice. The clinical community treating adults with ALL is small and specialist in nature, such that a panel size of four or five experienced clinicians per country was considered pragmatic and appropriate. The findings based on data collected in France, Germany, and the UK are presented here, as the panels in these countries described similar patterns of practice in treating BCP-ALL and were aligned on definitions of cure. The findings from Italy and Australia were distinct in their definition of cure and will be described in a separate publication.
This report therefore describes the findings of this study for three European countries. In summary, the study aimed to better understand how cure can be defined in adult BCP-ALL for patients in first complete hematological remission and in the context of clinical practice in each country, to inform evaluation of the clinical and economic benefits of emerging agents, specifically immunotherapies.