Day 15 bone marrow minimal residual disease predicts response to blinatumomab in relapsed/refractory paediatric B‐ALL

Relapse of B-cell precursor acute lymphoblastic leukaemia (B-ALL) occurs in approximately 10% to 15% of children and young adults (Pui et al., 2011; Schrappe et al., 2012; Hunger & Mullighan, 2015) and is an unsolved clinical problem. A five-year survival rate in children and young adults with relapsed disease is approximately 50% and further declines to 10% after two or more relapses (Reismüller et al., 2013; Rheingold et al., 2019). CD19 is stably expressed in B-ALL and is a rational target for immunotherapy (Raponi et al., 2011 Topp et al., 2012). Effector memory T cells have the potential to kill autologous tumour cells, and deep molecular remission [i.e., elimination of minimal residual disease (MRD)] has been shown to predict outcomes for patients with B-ALL (von Stackelberg et al., 2016; Berry et al., 2017). Blinatumomab (Blincyto®, Amgen Inc., Thousand Oaks, CA, USA) is a bispecific CD19/CD3 T-cell engager (BiTE®) immunotherapy that has been shown to induce MRD-negative remissions in adults with relapsed B-ALL or MRD-positive primary B-ALL (Topp et al., 2011; Topp et al., 2012). Blinatumomab is an established treatment for children with relapsed/refractory B-ALL, based on results from the phase 1/2, open-label, single-arm MT103-205 study (NCT01471782) (von Stackelberg et al., 2016) and has regulatory approval for this patient population in the US, European Union, Canada, Australia and Japan. Early predictors of response to blinatumomab in children with relapsed/refractory B-ALL would allow for more personalised and effective therapy, most importantly by facilitating timely pursuit of alternative therapies for patients unlikely to benefit from the continuation of single-agent blinatumomab. We therefore performed a post hoc analysis of data from the MT103-205 study (von Stackelberg et al., 2016) with the objective of assessing various early response parameters as potential predictors of subsequent response to blinatumomab. Key inclusion criteria for the MT103-205 study were B-ALL with M3 marrow (>25% leukaemic cells); age <18 years at study entry; and relapsed/refractory disease, specifically ≥2nd bone marrow (BM) relapse, any relapse after haematopoietic stem cell transplantation, or refractory to standard induction/reinduction. Key exclusion criteria were active acute or extensive chronic graft-versus-host disease after haematopoietic stem cell transplantation; active central nervous system or testicular involvement; or a history of or a current relevant central nervous system pathology. Patients were administered blinatumomab in six-week treatment cycles (four weeks on, two weeks off). A ‘rolling 6’ dose-escalation phase 1 was followed by a phase 2 evaluation of efficacy and toxicity (Figure S1). BM assessments were performed after each cycle. Morphologic responses were assessed locally and were confirmed by a central reference laboratory. MRD was assessed by central laboratories based on flow cytometry (von Stackelberg et al., 2016). The study protocol was approved by the institutional review board or independent ethics committee at each centre, and patients’ legal representatives gave written informed consent. The primary results of this study were previously published (von Stackelberg et al., 2016) and are summarised in Table SI. A total of 70 patients were treated at the recommended phase 2 dose of 5 µg/m2/day for the first seven days, followed by 15 µg/m2/day thereafter. Of these, 64 had response assessments (six did not have an assessment due to death or withdrawal of consent). The early response parameters assessed include: (i) peripheral blood (PB) morphology at day 8, (ii) BM morphology at days 15 and 29 and (iii) BM MRD at days 15 and 29. We assessed the degree to which each of these parameters predicted complete MRD response (defined as undetectable MRD within the first two cycles of blinatumomab). The day 15 BM MRD emerged as the most powerful predictor of response. Of the 64 patients with response assessments, 59 had day 15 BM MRD results available (Fig 1). Categorising the day 15 BM data as MRD-positive (MRD ≥ 10−4) or MRD-negative (MRD < 10−4), 46 patients were MRD-positive and 13 were MRD-negative. A comparison of the baseline characteristics of the MRD-positive and MRD-negative groups is shown in Table SII. The day 15 BM MRD predicted complete MRD response within two treatment cycles with 95% accuracy (correctly in 56 of 59 patients; Fig 1). For MRD-positive patients, complete MRD response rate was two out of 46 patients (4%), accurately predicting failure in 96% (44/46) of patients. Two MRD-positive patients (with day 15 MRD levels of 2·0 × 10–3 and 8·0 × 10–3) achieved complete MRD response within the second cycle, one on day 15 and the other on day 29, respectively. For MRD-negative patients, the complete MRD response rate was 12 of 13 patients, accurately predicting success in 92% of patients. In the patient with negative BM MRD on day 15 but with no subsequent complete MRD response, MRD levels increased through cycles 1 and 2, with a level of 4·3 × 10−2 on day 29 of cycle 1 and a level of 5·7 × 10−1 on day 29 of cycle 2. Other early response parameters analysed were less accurate predictors of complete MRD response (accuracy range: 49–90%; Table 1). Day 8 PB morphology was an especially poor predictor of subsequent response, with an accuracy of 49% (19 of 39 patients). Day 15 BM morphology (M1) had an accuracy of 90% (54 of 60 patients). Day 29 BM morphology (M1) had an accuracy of 84% (42 of 50 patients). Day 29 BM MRD (<10−4) had an accuracy of 86% (42 of 49 patients). Achieved indicated early response n (%) Complete MRD response n (%) In our analysis, day 15 BM MRD predicted complete MRD response to blinatumomab within the first two treatment cycles in a highly refractory paediatric B-ALL population. This is significant, as patients with BM MRD ≥ 10−4 at day 15, which is ultimately predictive of survival, could potentially pursue alternative therapies, such as dose escalation or combination therapies to achieve deeper remission. These data suggest that day 15 BM MRD results may allow personalised treatment and improve outcomes in paediatric patients with relapsed/refractory B-ALL. Larger studies and additional long-term outcome observations are warranted to confirm these findings and to help provide context to future therapeutic strategies for paediatric B-ALL. This work was funded by Amgen. The authors would like to acknowledge the patients, families, friends, caregivers, study staff and study investigators for their participation in this study. Medical writing assistance was provided by Julie Gegner (of Amgen Inc.) and Martha Mutomba (on behalf of Amgen Inc.). PB designed this study, analysed data, drafted the letter to the editor, and had full access to the data in the study. GZ, LG, CAT and AvS contributed to the study design, data analysis, as well as reviewing and providing substantial contributions during drafting of the letter. All authors approved the final draft of the letter and gave permission to submit to British Journal of Haematology. This work was supported by Amgen Inc. PB participated in advisory boards for Amgen, Novartis, Shire, and Jazz. GZ is an employee of Amgen GmbH and holds stock, patents and other intellectual property in Amgen. LG received advisory board/consulting fees from Amgen, Novartis Corp., Celgene Corp., and Roche/Genentech; has stock and stock options in Amgen, Anchiano, Clovis Oncology, Mirati, OnKure, and Sanofi Paris and is a member of the board of directors for Roundup River Ranch/SeriousFun Network. CAT is an employee of and holds stock/stock options in Amgen. AvS participated in advisory boards for Amgen, Roche, Shire, and Pfizer; and participated on the speakers’ bureaus for Amgen and Shire. Table SI. Efficacy outcomes in patients enrolled in the MT103-205 phase 1/2 study. Table SII. Baseline characteristics of patients categorised as MRD-positive (MRD ≥ 10−4) and MRD-negative (MRD < 10−4) by day 15 bone marrow data. Fig S1. MT103-205 phase 1/2 study design. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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