The availability and use of blinatumomab symbolizes a paradigm shift in the management of B-cell acute lymphoblastic leukemia (ALL). We conducted a retrospective multicenter cohort analysis of 239 ALL patients (227 relapsed refractory [RR], n = 227; minimal residual disease [MRD], n = 12) who received blinatumomab outside of clinical trials to evaluate safety and efficacy in the “real-world” setting. The median age of patients at blinatumomab initiation was 48 years (range, 18-85). Sixty-one (26%) patients had ≥3 prior therapies and 46 (19%) had allogeneic hematopoietic cell transplantation before blinatumomab. The response rate (complete remission/complete remission with incomplete count recovery) in patients with RR disease was 65% (47% MRD−). Among 12 patients who received blinatumomab for MRD, 9 (75%) patients achieved MRD negativity. In patients with RR disease, median relapse-free survival and overall survival (OS) after blinatumomab was 32 months and 12.7 months, respectively. Among patients who received blinatumomab for MRD, median relapse-free survival was not reached (54% MRD− at 2 years) and OS was 34.7 months. Grade ≥3 cytokine release syndrome, neurotoxicity, and hepatotoxicity were observed in 3%, 7%, and 10% of patients, respectively. Among patients who achieved complete remission/complete remission with incomplete count recovery, consolidation therapy with allogeneic hematopoietic cell transplantation retained favorable prognostic significance for OS (hazard ratio, 0.54; 95% confidence interval, 0.30-0.97; P = .04). In this largest “real-world” experience published to date, blinatumomab demonstrated responses comparable to those reported in clinical trials. The optimal sequencing of newer therapies in ALL requires further study.

Background The availability of novel agents (NAs), including blinatumomab and inotuzumab ozogamicin (InO), has improved the outcomes of patients with relapsed/refractory (RR) B‐cell acute lymphoblastic leukemia (ALL). Because of the relative effectiveness, it is often a challenge for clinicians to determine how to best sequence these NAs with respect to efficacy and toxicity. Methods In this multicenter, retrospective study of patients with RR ALL treated with blinatumomab, InO, or both, their efficacy as a first or second NA was compared. Results Among 276 patients, 221 and 55 received blinatumomab and InO, respectively, as a first NA therapy. The complete remission (CR)/complete remission with incomplete count recovery (CRi) rate was 65% and 67% for the blinatumomab and InO groups, respectively (P = .73). The rate of treatment discontinuation due to adverse events was 4% and 7% in the blinatumomab and InO groups, respectively. Ninety‐two patients (43%) in the blinatumomab group and 13 patients (29%) in the InO group proceeded with allogeneic hematopoietic stem cell transplantation. The median overall survival (OS) was 15 and 11.6 months in the blinatumomab and InO groups, respectively. A subset analysis was performed for 61 patients who received both NAs (blinatumomab and then InO [n = 40] or InO and then blinatumomab [n = 21]). The CR/CRi rate was 58% for patients who received InO as the second NA and 52% for patients who received blinatumomab as the second NA. The median OS was 10.5 for patients who received InO as the second NA and 5.9 months for patients who received blinatumomab as the second NA (P = .09). Conclusions Although the limited power of this study to detect a significant difference between subgroups is acknowledged, the data suggest that blinatumomab and InO may have comparable efficacy as a first or second NA therapy in RR ALL.

To minimize adverse events (AEs) unrelated to drugs and maximize the likelihood of drug approvals, eligibility criteria for randomized controlled trials (RCTs) may be overly restrictive. The purpose of this study was to determine if RCTs in hematologic malignancies exclude patients irrespective of known toxicities or observed AEs. MEDLINE was searched from 1/2010 to 1/2015 for RCTs published in high-impact journals. Of 97 trials, 33% were conducted in leukemia, 28% in lymphoma, 34% in multiple myeloma and 5% in myelodysplastic syndromes or myelofibrosis. Expected toxicities at thresholds of ⩾10%, ⩾5% and <5% were not correlated with cardiac, hepatic or renal eligibility criteria (logistic regression). To explore this lack of correlation we tested the concordance of expected toxicities and eligibility criteria using a modified version of McNemar's test: at each threshold, hepatic, renal and cardiac expected toxicities were significantly discordant with eligibility criteria. Hepatic and renal eligibility criteria were also not correlated with observed AEs, P=0.69 and P=0.77, respectively, but a significant correlation was detected between cardiac eligibility criteria and observed AEs, P=0.02. Thus, the analyzed RCTs excluding patients with organ dysfunction do not reflect expected toxicities, based on prescription drug labels/prior experience, or reported AEs on the trials.

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