Search

Importance: Blinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule with efficacy in children with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). Objective: To evaluate event-free survival in children with high-risk first-relapse B-ALL after a third consolidation course with blinatumomab vs consolidation chemotherapy before allogeneic hematopoietic stem cell transplant. Design, Setting, and Participants: In this randomized phase 3 clinical trial, patients were enrolled November 2015 to July 2019 (data cutoff, July 17, 2019). Investigators at 47 centers in 13 countries enrolled children older than 28 days and younger than 18 years with high-risk first-relapse B-ALL in morphologic complete remission (M1 marrow

Blinatumomab is the first-and-only Food and Drug Administration (FDA)-approved cluster of differentiation (CD) 19-directed CD3 bispecific T-cell engager (BiTE®) immunotherapy. It is currently FDA approved for the treatment of adults and children with Philadelphia chromosome-positive (Ph+) and Philadelphia chromosome-negative (Ph−) relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL) and B-cell precursor ALL with minimal residual disease. Similarly, initial marketing authorization for blinatumomab in the European Union was granted for the treatment of adults with Ph− R/R B-cell precursor ALL. The benefits of treating R/R B-cell precursor ALL patients with blinatumomab include increased overall survival, more favorable hematologic remission and molecular response rates, and a lower incidence rate of selected adverse events when compared with standard-of-care chemotherapy. The key risks associated with blinatumomab treatment include cytokine release syndrome, neurotoxicity, and medication errors. Here, we review the benefits and risks of blinatumomab treatment and describe how these risks can be mitigated.

Background: Children with high-risk 1st relapse B-ALL after frontline chemotherapy have a poor prognosis and are candidates for allogeneic hematopoietic stem cell transplant (alloHSCT) after achieving complete remission (CR). We previously reported that treatment with blinatumomab, a CD3/CD19-directed BiTE ® (bispecific T-cell engager) molecule, resulted in superior efficacy in event-free survival (EFS) and minimal residual disease (MRD) remission vs intensive multidrug chemotherapy as the 3rd consolidation block before alloHSCT in children with high-risk 1st relapse B-ALL in a phase 3 RCT (JAMA 2021;325:843-54).Here we provide FU of EFS, overall survival (OS), and safety as of Sep 2020, ie, beyond the July 2019 primary analysis. Methods: In this phase 3 RCT (Amgen NCT02393859), children >28 days and Results: Enrollment was terminated based on the interim analysis for benefit of blinatumomab (7/17/19 primary analysis). The following results reflect an updated analysis as of 9/14/20. Between Nov 2015-Aug 2019, 111 patients were randomized; 54 (49%) received blinatumomab and 57 (51%) received chemotherapy at 47 centers in 13 countries. Baseline characteristics were comparable in both arms (Table 1). After a median FU of 31 months, EFS was significantly superior with blinatumomab vs chemotherapy [63% vs 37%, stratified log-rank p CAR-T cell treatment after investigational therapy was reported for some patients; blinatumomab arm: 2/54 and chemotherapy arm: 9/57 patients (Table 2). Both blinatumomab arm patients had CD19+ disease after blinatumomab treatment, with OS of 22.1 and 12.8 months, and 1/2 alive at last FU. Of the 5 patients in the chemotherapy arm who later received blinatumomab, 3 had CD19+ disease after chemotherapy and 2 did not have CD19 expression data available; OS for these 5 patients ranged from 11.1-22.9 months with 2/5 alive at last FU. There were also 3 patients in the chemotherapy arm (but no exposure to blinatumomab) with CD19+ relapse who received CAR-T at relapse; OS for these patients ranged from 18.8-28.0 months and 2/3 were alive at last FU; a fourth patient with CD19-negative relapse who received chemotherapy only at relapse had OS of 24.8 months. Summary/Conclusion: In children with high-risk 1st relapse B-ALL, treatment with 1 cycle of blinatumomab vs chemotherapy before alloHSCT resulted in significantly superior EFS and improved OS. The incidence of CD19-negative relapse after blinatumomab was low. No evidence of a negative impact of blinatumomab followed by CAR-T cell therapy was noted in this small subset of patients. Figure 1 Figure 1. Disclosures Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau. Zugmaier: Amgen: Current Employment; Micromet/Amgen: Patents & Royalties: Patents 20190300609 and 20130323247 licensed; receives royalties of family members of international applications published as WO2010/052014; WO2010/052013; WO2011/051307; WO2012/055961; WO 2012/062596; WO2014/122251; and WO2015/181683; Amgen: Current equity holder in publicly-traded company. Rizzari: Sobi: Other: personal fees; Shire: Other: Grants and personal fees; Medac: Other: Grants and personal fees; Jazz Pharmaceuticals: Other: Personal fees; Amgen: Other: Personal fees. Morris: Amgen: Current Employment. Gruhn: AmgenGmbh: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel costs; Bellicum Pharma Gmbh: Membership on an entity's Board of Directors or advisory committees, Other: travel costs; EUSA Pharma Gmbh: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Other: travel costs; Novartis Pharma Inc.: Honoraria, Other: travel costs; pfizer: Honoraria; servier: Honoraria, Other: travel costs; Neovii Biotech GmbH: Other: travel costs; medac GmbH: Other: travel costs. Zeng: Amgen: Current Employment. Pilankar: Iqvia: Current Employment, Other: Iqvia provides support for Amgen. Kormany: Amgen: Current Employment. Moericke: Amgen: Other: Grants; Shire: Other: Personal fees. Peters: Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants. Saha: Amgen: Other: Personal fees. von Stackelberg: Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Miltenyi: Consultancy, Honoraria.

Background: Blinatumomab is approved for the treatment of adult patients (pts) with relapsed/refractory Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukaemia (R/R Ph- BCP-ALL). We present interim 3-year results of a multi-country observational study in R/R Ph- BCP-ALL pts, including the subset with late first relapse (LFR, defined as first remission duration of ≥12 months [mos]). LFR pts were excluded from the pivotal studies of R/R Ph- BCP-ALL and data is limited on blinatumomab treatment outcomes in this population. Methods: This study included adult pts who initiated blinatumomab between 22 March 2017 and 12 February 2020 in routine clinical practice. Pts who received blinatumomab in a clinical trial or an expanded access program were excluded. Informed consent was sought according to local guidelines. Data was extracted from medical records: pts were categorized as LFR by the treating clinicians. Pts were followed-up until data cut-off date, death, loss-to-follow-up, or withdrawal: whichever came first. Denominators of percentages excluded pts with missing data unless indicated. Kaplan-Meier (KM) estimates were calculated to investigate survival outcomes at 24 mos: relapse-free survival (RFS) defined as the interval between complete remission with full/partial/incomplete recovery of peripheral blood counts (CR/CRh/CRi) and relapse (bone marrow blasts >5%) or death; and overall survival (OS) defined as the interval from blinatumomab initiation to death. Cumulative Incidence Function (CIF) estimates were calculated for: mortality (independent of relapse) following allogeneic haematologic stem cell transplant (alloHSCT), and relapse (independent of unrelated death) after alloHSCT. Results: A total of 118 R/R Ph- pts were included: median age was 45.5 years (interquartile range [IQR]: 29.0, 58.0) with 47.5% (n=56) being female. For the subset of R/R Ph- pts with LFR (n=38), median age was 34.5 years (IQR: 23.0, 50.0) with 50.0% being female. Among all pts: 22% (n=26) had previous HSCT (28.9% [n=11] in the LFR subset), 100% (n=118) were treated with ≥1 prior anti-cancer therapy, 42.4% (n=50) underwent first salvage, 8.5% (n=10) second salvage, and 0.8% (n=1) third salvage. Within 2 blinatumomab cycles, 73.7% (n=87) R/R Ph- pts achieved CR/CRh/CRi: among CR/CRh/CRi pts with evaluable minimal residual disease (MRD, n=44), 45.5% had MRD response (Table). The majority (78.5%, n=62) of pts proceeded to alloHSCT, of whom 64.5% (n=40) had achieved CR/CRh/CRi and had no additional myelosuppressive therapy (Table). The KM estimates for RFS and OS at 24 mos were 50.0% (95% confidence interval [CI]: 37.0, 62.0) and 58.0% (95% CI: 46.0, 68.0), respectively. In pts who achieved CR/CRh/CRi and had no additional therapy before proceeding to alloHSCT, the CIF estimates for relapse and mortality at 1 year following alloHSCT were 8.0% (95% CI: 2.0, 20.0) and 13.0% (95% CI: 5.0, 26.0) respectively. In the LFR subset, 78.9% (n=30) achieved CR/CRh/CRi within 2 cycles: among evaluable pts (n=15) 73.3% (n=11) had MRD response (Table). Most pts (83.3%, n=25) proceeded to alloHSCT, of whom 77.3% (n=17) had achieved CR/CRh/CRi and had no additional myelosuppressive therapy (Table). At 24 mos, the KM estimates for RFS and OS were 70.0% (95% CI: 47.0, 85.0) and 74.0% (95% CI: 51.0, 87.0), respectively. In pts who achieved CR and proceeded to alloHSCT without other therapy, the CIF estimates for relapse and mortality at 1 year were both 7.0% (95% CI: 0.0, 27.0). Among R/R Ph- pts, 89.8% (n=106) had adverse events (AEs) occurring between blinatumomab initiation and ≤30 days following the final infusion, 36.4% (n=43) reported serious AEs (SAEs) and 5.9% (n=7) fatal events: 1 fatal AE was blinatumomab-related. AEs were reported in 86.8% of LFR pts (n=33), and 28.9% (n=11) of pts experienced an SAE (no fatal events occurred). In both subgroups, the most commonly reported AEs (in >34% of pts) were infusion reactions (including cytokine release syndrome), serious infections, and neurological events (Table). Conclusion: In real-world clinical practice, blinatumomab was an effective therapy in pts with R/R Ph- ALL including those with LFR. Almost three quarters of pts achieved CR/CRh/CRi within two cycles. Most pts proceeded to alloHSCT, the majority in CR/CRh/CRi and without additional myelosuppressive therapy. The safety data are consistent with the established safety profile of blinatumomab. Disclosures Rijneveld: Servier: Research Funding; Amgen: Research Funding. Fracchiolla:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; ABBVIE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses. Šálek:Amgen: Consultancy, Honoraria, Research Funding. Chiaretti:Amgen: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees. Alam:Amgen: Current Employment, Current equity holder in publicly-traded company. Pezzani Grueter:Amgen: Current Employment, Current equity holder in publicly-traded company, Other: Travel, accommodations, expenses. Mohammad:Amgen: Current Employment, Current equity holder in publicly-traded company. Kormany:Amgen: Current Employment, Current equity holder in publicly-traded company. Kreuzbauer:Amgen: Current Employment, Current equity holder in publicly-traded company. Rambaldi:Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); University of Milan: Current Employment; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company).

Introduction: The open-label, expanded access study (RIALTO) demonstrated that blinatumomab is efficacious with a manageable safety profile in children with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R BCP-ALL). Blinatumomab is a BiTE® (bispecific T-cell engager) immuno-oncology therapy that activates cytotoxic T cells to kill target B cells. Here, findings from the final analysis of RIALTO are presented (NCT02187354). Methods: Enrolled in the study were children >28 days and Results: As of the data cutoff date (January 10, 2020) for the final analysis, demographics and baseline characteristics of 110 patients enrolled (median age, 8.5 years [95% CI 0.4-17.0]), 61% had For best treatment response within the first 2 cycles, results are comparable to that of the primary analysis. Among 110 patients, overall CR rate was 62.7% (n= 69). Of 98 patients with ≥5% blasts at baseline, 59% (n=58) achieved CR; of them, 79% (n=46) achieved an MRD response and 62% (n=39) proceeded to HSCT. The 2 patients with t(17;19) achieved CR with an MRD response. Of the 4 patients with germline trisomy 21 (Down syndrome), 3 achieved CR with an MRD response Among the 12 patients with Of 110 patients treated with blinatumomab, median OS (95% CI) was 14.6 (11-24.5) months with median follow-up time of 18.2 months, which increased by 1.5 months compared with that reported in the primary analysis, with 29.9% of patients still surviving at month 24. Median RFS (95% CI) remains unchanged at 8.5 months (4.7-14.0), with a median follow-up time of 11.5 months in patients who achieved CR; 38% of patients relapsed and 9% died. RFS was more favorable for patients who received HSCT post blinatumomab (70%) than for those who did not (30%) at month 12, respectively, which is consistent with the results from primary analysis. Among patients who had HSCT prior to blinatumomab (n= 45), median OS (95%) was 16.6 (7.1-NE) months vs 14.6 (10.9-24.5) months in patients without HSCT prior to blinatumomab (n= 65). Compared with the primary analysis, 5 additional patients received HSCT after achieving CR in the final analysis. Median OS among patients in CR after HSCT by MRD responders vs MRD non-responders was NE at 15-month analysis (Figure). Safety results in the final analysis were consistent with those reported in the primary analysis. Of 110 patients, 99% experienced TEAEs, with 65% being grade ≥3 (see Table 3 for details). TRAEs were reported in 74% of patients; 26% were grade ≥3 and 19% were deemed serious. Details on grade ≥3 TRAEs are shown in Table 3. The 9 fatal AEs, unrelated to blinatumomab, occurred due to relapse and progressive nature of the disease (Table 3). Conclusions: Overall, the safety and efficacy results from the final analysis are consistent with those reported in the primary analysis as no new safety signals were observed. These findings strengthen the observation that blinatumomab demonstrates durable efficacy and is a suitable treatment option in children with R/R BCP-ALL. Table 1. Disclosures Locatelli: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceeutical: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zugmaier:Amgen: Current Employment, Other: Personal Fees ; 20190300609: Patents & Royalties: Licensed patient . Mergen:Amgen: Current Employment, Current equity holder in publicly-traded company. Bader:Medac: Patents & Royalties, Research Funding; Amgen: Consultancy, Speakers Bureau; Neovii: Research Funding; Celgene: Consultancy; Novartis: Consultancy, Speakers Bureau; Riemser: Research Funding. Schlegel:bluebird bio: Honoraria. Bourquin:Servier: Other: Travel Support. Handgretinger:Amgen: Honoraria. Brethon:Amgen: Other: invitation to meetings, remunerations for oral presentations, advices for the record of Blinatumomab in pediatrics in France. Rössig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Pfizer: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Kormany:Amgen: Current Employment, Current equity holder in publicly-traded company. Viswagnachar:IQVIA: Current Employment.

7032 Background: Blinatumomab (blin), a bispecific T-cell engaging antibody construct, has shown improved overall survival vs SOC in pts with r/r ALL in a randomized phase 3 study ( Haematologica 2016;101:S129). To better evaluate safety, we compared AEs of blin vs SOC after adjusting for varying treatment exposure times. Methods: Adults ≥ 18 yrs with r/r ALL (refractory, 1st relapse < 1 yr, ≥ 2 relapses or relapse after transplant) were randomized to receive blin or SOC (1 of 4 predefined regimens). Blin was dosed by continuous infusion (4 wks on/2 wks off) for up to 5 cycles (9 µg/d on d1−7 in cycle 1, then 28 µg/d); up to 4 maintenance cycles (4 wks on/8 wks off) were allowed for ≤ 12 mo. Exposure-adjusted (exp-adj) event rates were calculated as no. of events*100/total exposure time (Table). Results: Median (range) no. of cycles were 1 (1−4) for SOC and 2 (1−9) for blin. The highest exp-adj rates (per 100 pt-yrs) were for pyrexia (507 SOC vs 376 blin), anemia (987 vs 229), thrombocytopenia (750 vs 126) and neutropenia (351 vs 121), all lower in blin. Febrile neutropenia (365 vs 93) and infections (1216 vs 436) were also both lower in blin (p < 0.0001). Exp-adj rates for neurologic events were 743 SOC vs 472 blin, with median time (range) to onset of 7 (1−43) d and 7 (1−190) d, respectively, and gr ≥ 3 cytokine release syndrome (CRS) rates were 0 SOC vs 10 blin. The most frequent AEs in both cycles 1 and 2 were pyrexia, nausea and anemia in both arms; CRS events decreased in the blin arm between cycles 1 and 2 (14% vs 2%). Most fatal AEs were related to infection in both arms. Conclusions: Here blin showed an AE profile consistent with that previously reported for r/r ALL, including similar rates of manageable CRS and neurologic events. Exp-adj AE rates were generally higher in SOC vs blin, including for cytopenias and infections. Clinical trial information: NCT02013167. [Table: see text]