OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 30 September 2017

Abbreviations used: ALL, acute lymphoblastic leukemia; HCT, hematopoietic cell transplantation.

• Zimmerman HJ. Hepatotoxic effects of oncotherapeutic and immunosuppressive agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 673-708.

  (Expert review of hepatotoxicity published in 1999, well before the availability of most monoclonal antibody therapies).
• Reuben A. Hepatotoxicity of immunosuppressive drugs. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2011, pp. 569-91.

  (Review of hepatotoxicity of immunosuppressive agents mentions rituximab and problems of reactivation of hepatitis B, but also states that "the biological immunosuppressants are largely free from hepatotoxicity, with the exception of the TNF alpha antagonists"; no specific discussion of blinatumomab).
• Chabner BA, Barnes J, Neal J, Olson E, Mujagiv H, Sequist L, Wilson W, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-53.

  (Textbook of pharmacology and therapeutics).
• Handgretinger R, Zugmaier G, Henze G, Kreyenberg H, Lang P, von Stackelberg A. Complete remission after blinatumomab-induced donor T-cell activation in three pediatric patients with post-transplant relapsed acute lymphoblastic leukemia. Leukemia 2011; 25: 181-4. [PubMed: 20944674]

  (3 children with refractory and relapsed B precursor ALL after HCT responded with complete remission after 4-6 weeks of infusions with blinatumomab with minimal adverse side effects).
• Topp MS, Kufer P, Gökbuget N, Goebeler M, Klinger M, Neumann S, Horst HA, et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol 2011; 29: 2493-8. [PubMed: 21576633]

  (Among 20 patients with relapsed ALL or with “minimal residual disease” who were treated with 59 cycles of blinatumomab, 16 had a molecular response but adverse events were frequent including lymphopenia, fever and hypokalemia, and one patient with transient ALT elevations above 5 times ULN).
• Topp MS, Gökbuget N, Zugmaier G, Degenhard E, Goebeler ME, Klinger M, Neumann SA, et al. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood 2012; 120: 5185-7. [PubMed: 23024237]

  (After a median follow up of 33 months, 61% of the 20 patients with ALL treated with blinatumomab [Topp 2011], were still relapse-free and no further adverse events were reported).
• Teachey DT, Rheingold SR, Maude SL, Zugmaier G, Barrett DM, Seif AE, Nichols KE, et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood 2013; 121: 5154-7. [PMC free article: PMC4123427] [PubMed: 23678006]

  (Analysis of clinical features and cytokine levels in a patient with ALL treated with blinatumomab thought to be cytokine release syndrome was considered to be macrophage activation syndrome [MAS] and rapidly responded to toclizumab [anti-IL6] therapy).
• Topp MS, Gökbuget N, Zugmaier G, Klappers P, Stelljes M, Neumann S, Viardot A, et al. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol 2014; 32: 4134-40. [PubMed: 25385737]

  (Among 36 patients with relapsed or refractory B-precursor ALL who were treated with blinatumomab, 69% achieved a complete response, and adverse events were common including fever [81%], fatigue [50%], headache [47%], tremor [36%] and leukopenia [19%]; no mention of ALT elevations or hepatotoxicity).
• Di Bisceglie AM, Lok AS, Martin P, Terrault N, Perrillo RP, Hoofnagle JH. Recent US Food and Drug Administration warnings on hepatitis B reactivation with immune-suppressing and anticancer drugs: just the tip of the iceberg? Hepatology 2015; 61: 703-11. [PMC free article: PMC5497492] [PubMed: 25412906]

  (Review of the pathogenesis, clinical course, treatment and prevention of HBV reactivation in patients receiving immunosuppressive or anticancer therapies, with particular focus on rituximab and ofatumumab; no mention of blinatumomab).
• Topp MS, Gökbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, Dombret H, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol 2015; 16: 57-66. [PubMed: 25524800]

  (Among 189 patients with refractory or relapsed B-precursor ALL treated with blinatumomab, 33% had a complete response, 2% had cytokine release syndrome, 11% neurological complications, and 13% had ALT elevations which were above 5 times ULN in 6%; no mention of clinically apparent hepatotoxicity).
• Zugmaier G, Gökbuget N, Klinger M, Viardot A, Stelljes M, Neumann S, Horst HA, et al. Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment. Blood 2015; 126: 2578-84. [PMC free article: PMC4671107] [PubMed: 26480933]

  (Among 36 adults with relapsed or refractor B-precursor ALL treated with blinatumomab, 10 [28%] were long term survivors and serious adverse events included convulsions, encephalopathy and cytokine release syndrome; no mention of ALT elevations or hepatotoxicity).
• Viardot A, Goebeler ME, Hess G, Neumann S, Pfreundschuh M, Adrian N, Zettl F, et al. Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. Blood 2016; 127: 1410-6. [PMC free article: PMC4797019] [PubMed: 26755709]

  (Among 21 patients with relapsed or refractory B-precursor ALL treated with blinatumomab, there were no liver related serious adverse events or deaths; ALT elevations were not reported).
• Goebeler ME, Knop S, Viardot A, Kufer P, Topp MS, Einsele H, Noppeney R, et al. Bispecific T-Cell engager (BiTE) antibody construct blinatumomab for the treatment of patients with relapsed/refractory non-Hodgkin lymphoma: final results from a phase I study. J Clin Oncol 2016; 34: 1104-11. [PubMed: 26884582]

  (Among 76 patients with relapsed or refractory non-Hodgkin lymphoma treated with blinatumomab, neurologic events were dose limiting and at 60 µg/m2 per day, the overall response rate was 69%, neurologic adverse events occurred in 22% and ALT elevations in 33%, but none were above 5 times ULN).
• Przepiorka D, Ko CW, Deisseroth A, Yancey CL, Candau-Chacon R, Chiu HJ, Gehrke BJ, Gomez-Broughton C, et al. FDA approval: blinatumomab. Clin Cancer Res 2015; 21: 4035-9. [PubMed: 26374073]

  (Summary of the clinical studies that supported the FDA approval of blinatumomab for treatment of relapsed or refractory precursor B cell ALL; summary safety results from 212 treated adults mentions ALT elevations occurring in more than 10% of patients, but that “elevated transaminases generally occurred in the setting of cytokine release syndrome”).
• Blinatumomab (Blincyto) for acute lymphoblastic leukemia. Med Lett Drugs Ther 2015; 57 (1468): e74-5. [PubMed: 25941958]

  (Concise summary of the mechanism of action, clinical efficacy, safety and costs of blinatumomab shortly after its approval in the US; no mention of ALT elevations or hepatotoxicity).
• von Stackelberg A, Locatelli F, Zugmaier G, Handgretinger R, Trippett TM, Rizzari C, Bader P, et al. Phase I/phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. J Clin Oncol 2016; 34: 4381-9. [PubMed: 27998223]

  (Among 93 pediatric patients with relapsed or refractory ALL treated with varying doses of blinatumomab, 39% had a complete response to the optimal dose and the most frequent serious adverse events were anemia, thrombocytopenia and hypokalemia, while 4 patients had cytokine release syndrome and 2 seizures; ALT elevations above 5 times ULN occurred in 16%).
• Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 2017; 376: 836-47. [PMC free article: PMC5881572] [PubMed: 28249141]

  (Among 405 patients with relapsed or refractory ALL treated with blinatumomab or standard chemotherapy, overall median survival was greater with blinatumomab [7.7 vs 4.0 months] and adverse events rates were similar [98.5% vs 99.1%]; although serious adverse events were higher with blinatumomab [62% vs 45%] but liver enzyme elevations were not [12.7% vs 14.7%]).
• Burki TK. Blinatumomab significantly improves overall survival. Lancet Oncol 2017; 18: e203. [PubMed: 28285842]

  (News report summarizing the controlled trial of blinatumomab that showed an improvement in overall survival in relapsed and refractory ALL [Kantarjian 2017]).
• Nägele V, Kratzer A, Zugmaier G, Holland C, Hijazi Y, Topp MS, Gökbuget N, et al. Changes in clinical laboratory parameters and pharmacodynamic markers in response to blinatumomab treatment of patients with relapsed/refractory ALL. Exp Hematol Oncol 2017; 6: 14. [PMC free article: PMC5437652] [PubMed: 28533941]

  (Among 36 adults with relapsed or refractory ALL treated with blinatumomab, ALT, AST and bilirubin levels rose within 24 hours of starting infusions and declined to baseline by the end of the cycle, but rose minimally with subsequent cycles, elevations being mild-to-moderate in degree and fully reversible, corresponding to the timing of cytokine release).