Introduction
The prognosis for adult patients with Philadelphia chromosome-negative (Ph[−]) B-precursor ALL who are refractory to treatment or experience relapse (R/R) is poor: over 90% die from the disease and their survival time is short (median OS is 3–5 months) [
1‐
4]. These patients tend to be particularly young, with a median age of 34–39 years, and die, on average, 30 years prematurely [
5‐
7]. In general, response to salvage treatment followed by hematopoietic stem cell transplant (HSCT) offers the only potential for cure and long-term survival [
1,
4]. Until recently, salvage treatment for adult patients with R/R Ph(−) B-precursor ALL was limited to highly toxic multi-agent chemotherapy regimens. Most patients who receive these regimens endure repeated and prolonged hospitalizations due to the severity of the disease and the aggressiveness of the treatment itself [
8‐
11].
Blinatumomab is a novel bispecific T cell engager (BiTE
®) antibody construct that simultaneously binds CD3-positive cytotoxic T cells and CD19-positive B cells. Blinatumomab was approved for adults with R/R Ph(−) B-cell precursor ALL by the FDA in December 2014 and subsequently by the European Medicines Agency (EMA) in November 2015 [
12,
13]. Regulatory approval of blinatumomab in the US was based on results from a single-arm phase 2 study in 189 adults with R/R Ph(−) B-precursor ALL [
14]. Historical observational data from 1139 patients with R/R Ph(−) B-precursor ALL who received standard of care therapy in Europe and the US provided context for the interpretation of the single-arm clinical study [
15]. The single-arm clinical study and the historical observational data have been compared for rates of complete remission (42.9% vs 24%) and overall survival (OS) at 1 (32.0% vs 15.5%) and 3 years (13.8% vs 6.2%) [
14,
15]. To date, the blinatumomab clinical study includes 3 years of survival follow-up data, after which time 13.8% of patients remained alive [Amgen data on file]. In comparison, 6.4% patients in the historical data were alive at 3 years. The historical observational dataset included up to 21 years of follow up, after which time between 2% and 3% of patients remained alive. Given the very small percentage of patients in the historical observational dataset who lived for at least 21 years, the proportion of patients receiving blinatumomab who were still alive after 3 years is of particular interest.
To estimate the effect of a treatment on long-term survival, the mean OS is a preferred endpoint to median OS because it captures the entire survival curve over the lifetime of a population [
16]. The objective of this analysis was to estimate the long-term survival of patients with R/R Ph(−) B-cell precursor ALL receiving blinatumomab, leveraging the long duration of follow-up data available in the historical observational dataset.
Discussion
This study estimated long-term survival for R/R Ph(−) ALL patients receiving blinatumomab, using both the blinatumomab clinical trial results and long-term natural history data. Assuming no additional effects of blinatumomab beyond two years, the percentage of long-term survivors treated with blinatumomab is estimated to be more than double that of patients treated with salvage chemotherapy (12.6% vs 5.4% after 5 years). The estimation technique was validated using an additional year of observed clinical trial data. Similarly, the mean OS—a measure of overall survival over the lifetime of the population—was also approximately doubled among blinatumomab-treated patients in comparison to patients in the historical observational dataset (76.1 vs 39.8 months).
The historical data set was pooled from European national study groups and large individual sites from Europe and the United States. Given rarity of R/R Ph(−) B–precursor ALL, the historical dataset represents the largest study of its kind in adults with this disease [
13,
15], spanning over 20 years (1990–2013), During this time, no new effective treatments have emerged [
3]. The increased use of paediatric-inspired protocols and improvements in supportive care and transplant realisation may have improved survival over time in some groups of adult R/R ALL patients [
19]. Two-thirds of patients in the historical dataset were diagnosed after the year 2000, the survival times were similar between the whole dataset and those patients diagnosed from 2000 onwards [
15]. The historical data therefore appears to provide a valid reference for survival data extrapolation and comparison between novel agents and salvage chemotherapy.
It is worth noting that the assumed difference in survival between blinatumomab and salvage chemotherapy after the observed data time period in this study might be an underestimation. After the observed OS data, we assumed that the patients treated with blinatumomab had the same conditional survival probability as patients who received salvage chemotherapy. In fact, patients receiving blinatumomab can achieve a deep response, which is known to correlate with better long-term survival outcomes [
20]. Among 81 patients with R/R Ph(−) B-precursor ALL who achieved complete remission (CR/CRh*), 82% also achieved minimal residual disease (MRD)-negativity within two cycles of blinatumomab [
14]. In an earlier clinical study of 36 patients with Ph(−) B-cell precursor R/R ALL, 28% of those treated with blinatumomab survived for at least 30 months, all of whom achieved an MRD-negative response [
21]. These findings suggest that patients treated with blinatumomab might have higher conditional survival probability than patients receiving salvage chemotherapy. More patients in the blinatumomab clinical study proceed to receive transplants, possibly due to favourable CR rate, or higher rate of MRD negativity [
14], which is highly correlated to positive HSCT outcome and better overall survival, compared to those who do not achieve MRD [
22,
23].
With 12.6% of R/R ALL patients treated with blinatumomab expected to be alive after 5 years other treatment strategies are still required. Treatment with blinatumomab before relapse has been shown to produce high response rates and survival outcomes: 78% of patients with MRD-positive disease achieved a complete MRD response after 1 cycle of blinatumomab, and RFS was 58% after 18 months [
24]. In a smaller study in an MRD-positive population, after a median of 33 months follow up, 61% of blinatumomab-treated patients remained relapse-free [
25]. These data raise the possibility that earlier intervention with blinatumomab may allow long-term remissions and reduce the need for salvage therapy.
The blinatumomab clinical trial enrolled R/R Ph(−) B-precursor ALL patients who were selected for negative prognostic factors, which represents the majority of patients but nonetheless a subset of the total R/R Ph(−) B-precursor ALL population. Caution needs to be taken when extrapolating the results from this study to the broader patient group.
Limitations of this study are inherent in the use of historical data to compare and extrapolate survival outcomes with data from a clinical study. These include the assumption of no additional effects of blinatumomab beyond two years, potential changes in treatment practices over time in the clinical vs historical populations and differences in transplant realisation rates. Nonetheless, the superior survival outcomes with blinatumomab treatment over standard of care have recently been confirmed in a phase 3 study [
26].
Acknowledgements
The study, article processing charges, and the open access charge were funded by Amgen. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. Editorial assistance in the preparation of this manuscript was provided by James O’Kelly, an employee of Amgen.