Impact of Blinatumomab Treatment on Bone Marrow Function in Patients with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia

Hagop M Kantarjian, Gerhard Zugmaier, Monika Brüggemann, Brent L Wood, Heinz A Horst, Yi Zeng, Giovanni Martinelli, Hagop M Kantarjian, Gerhard Zugmaier, Monika Brüggemann, Brent L Wood, Heinz A Horst, Yi Zeng, Giovanni Martinelli

Abstract

Association of blinatumomab treatment with myelosuppression was examined in this study. Peripheral blood counts were assessed prior to, during, and after blinatumomab treatment in patients with relapsed/refractory Philadelphia chromosome-negative (Ph-) B-cell precursor (BCP) acute lymphoblastic leukemia (ALL; n = 267) and Ph+ BCP-ALL (n = 45) from the TOWER and ALCANTARA studies, respectively, or chemotherapy in patients with Ph- BCP-ALL (n = 109) from the TOWER study; all the patients with relapsed/refractory BCP-ALL and responders achieving complete remission (CR) or CR with partial/incomplete hematological recovery (CRh/CRi) were evaluated. Event-free survival (EFS) and overall survival (OS) were assessed in patients achieving CR and CRh/CRi. Median leukocyte, neutrophil, and platelet counts increased during two blinatumomab cycles but remained low longer after chemotherapy. Among the responders, there was a trend that a greater proportion of patients achieved CR with blinatumomab (Ph-, 76.5%; Ph+, 77.8%) versus with chemotherapy (Ph-, 63.6%). In the TOWER study, the survival prognosis for patients achieving CRh/CRi versus CR with blinatumomab was more similar (median OS, 11.9 (95% CI, 3.9-not estimable (NE)) vs. 15.0 (95% CI, 10.4-NE) months, p = 0.062) than with chemotherapy (5.2 (95% CI, 1.6-NE) vs. 18.9 (95% CI, 9.3-NE) months, p = 0.013). Blinatumomab treatment, with only temporary and transient myelosuppression, resulted in a greater survival benefit than chemotherapy.

Keywords: acute lymphoblastic leukemia; bispecific T-cell engager; bispecific antibody; blinatumomab; measurable residual disease; myelosuppression.

Conflict of interest statement

H.M.K. reports research funding from AbbVie, Agios Pharmaceuticals, Amgen, Ariad Pharmaceuticals, Astex Pharmaceuticals, Bristol-Myers Squibb, Cyclacel Pharmaceuticals, Daiichi-Sankyo, ImmunoGen, Jazz Pharmaceuticals, Novartis, and Pfizer and honoraria from AbbVie, Actinium Pharmaceuticals, Agios Pharmaceuticals, Amgen, ImmunoGen, Orsenix, Pfizer, and Takeda. G.Z. is an employee and stockholder of Amgen and reports patents. M.B. reports research funding from Affimed, Amgen, Regeneron and honoraria from Amgen, Becton Dickinson, Janssen, Incyte, Celgene, and Novartis. B.L.W. receives honoraria from Amgen and Beckman-Coulter and contract research funding from Amgen, Novartis, Kite, MacroGenics, BioSight, and Celgene. H.A.H. reports research funding and travel support from and participation in advisory boards for Amgen, participation in advisory boards for Pfizer, Jazz Pharmaceuticals, and Novartis, and research funding from Regeneron. Y.Z. is an employee and stockholder of Amgen. G.M. declares no known competing financial interests.

Figures

Figure 1
Figure 1
Peripheral blood counts of responders at baseline, during and after two treatment cycles with blinatumomab or chemotherapy. The median WBC of the Ph− (A) and Ph+ (B) responders, median ANC of the Ph− (C) and Ph+ (D) responders, and the median platelet count of the Ph− (E) and Ph+ (F) responders were plotted at baseline, on the cycle and day of treatment assessed, and at the SFU visit 30 days after treatment. Vertical lines represent the first and third quartiles around the median. ANC, absolute neutrophil count; C, cycle; D, day; Ph+, Philadelphia chromosome-positive; Ph−, Philadelphia chromosome-negative; SFU, safety follow-up; WBC, white blood cell.
Figure 2
Figure 2
Blinatumomab treatment results in a higher proportion of CR among responders. The proportion of patients achieving CR relative to those achieving CRh/CRi was assessed in the patients with Ph+ R/R BCP ALL treated with blinatumomab from the ALCANTARA trial [27] or the patients with Ph− R/R BCP ALL treated with blinatumomab or chemotherapy from the TOWER trial [12]. ALL, acute lymphoblastic leukemia; BCP, B-cell precursor; CR, complete remission; CRh, CR with partial recovery of peripheral blood counts; CRi, CR with incomplete recovery of peripheral blood counts; Ph+, Philadelphia chromosome-positive; Ph−, Philadelphia chromosome-negative; R/R, relapsed/refractory.
Figure 3
Figure 3
EFS analyzed according to the response within 12 weeks of treatment with blinatumomab or chemotherapy in the patients with Ph− R/R BCP ALL. ALL, acute lymphoblastic leukemia; BCP, B-cell precursor; CI, confidence interval; CR, complete remission; CRh, CR with partial recovery of peripheral blood counts; CRi, CR with incomplete recovery of peripheral blood counts; EFS, event-free survival; Ph−, Philadelphia chromosome-negative; R/R, relapsed/refractory.
Figure 4
Figure 4
OS analyzed according to the response within 12 weeks of treatment with blinatumomab or chemotherapy in the patients with Ph− R/R BCP ALL. ALL, acute lymphoblastic leukemia; BCP, B-cell precursor; CI, confidence interval; CR, complete remission; CRh, CR with partial recovery of peripheral blood counts; CRi, CR with incomplete recovery of peripheral blood counts; NE, not estimable; OS, overall survival; Ph−, Philadelphia chromosome-negative; R/R, relapsed/refractory.

References

    1. Matsushima S., Kobayashi R., Sano H., Hori D., Yanagi M., Kodama K., Suzuki D., Kobayashi K. Comparison of myelosuppression using the D-index between children and adolescents/young adults with acute lymphoblastic leukemia during induction chemotherapy. Pediatr. Blood Cancer. 2021;68:e28763. doi: 10.1002/pbc.28763.
    1. Glisovic S.J., Pastore Y.D., Gagne V., Plesa M., Laverdière C., Leclerc J.M., Sinnett D., Krajinovic M. Impact of genetic polymorphisms determining leukocyte/neutrophil count on chemotherapy toxicity. Pharmacogenomics J. 2018;18:270–274. doi: 10.1038/tpj.2017.16.
    1. Dolan G., Lilleyman J.S., Richards S.M. Prognostic importance of myelosuppression during maintenance treatment of lymphoblastic leukaemia. Leukaemia in Childhood Working Party of the Medical Research Council. Arch. Dis. Child. 1989;64:1231–1234. doi: 10.1136/adc.64.9.1231.
    1. Crawford J., Dale D.C., Lyman G.H. Chemotherapy-induced neutropenia: Risks, consequences, and new directions for its management. Cancer. 2004;100:228–237. doi: 10.1002/cncr.11882.
    1. Nägele V., Kratzer A., Zugmaier G., Holland C., Hijazi Y., Topp M.S., Gökbuget N., Baeuerle P.A., Kufer P., Wolf A., 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. doi: 10.1186/s40164-017-0074-5.
    1. Lustberg M.B. Management of neutropenia in cancer patients. Clin. Adv. Hematol. Oncol. 2012;10:825–826.
    1. Nesher L., Rolston K.V. The current spectrum of infection in cancer patients with chemotherapy related neutropenia. Infection. 2014;42:5–13. doi: 10.1007/s15010-013-0525-9.
    1. Bochud P.Y., Eggiman P., Calandra T., Van Melle G., Saghafi L., Francioli P. Bacteremia due to viridans streptococcus in neutropenic patients with cancer: Clinical spectrum and risk factors. Clin. Infect. Dis. 1994;18:25–31. doi: 10.1093/clinids/18.1.25.
    1. Gómez H., Hidalgo M., Casanova L., Colomer R., Pen D.L., Otero J., Rodríguez W., Carracedo C., Cortés-Funes H., Vallejos C. Risk factors for treatment-related death in elderly patients with aggressive non-Hodgkin’s lymphoma: Results of a multivariate analysis. J. Clin. Oncol. 1998;16:2065–2069. doi: 10.1200/JCO.1998.16.6.2065.
    1. Liu W., Zhang C.C., Li K. Prognostic value of chemotherapy-induced leukopenia in small-cell lung cancer. Cancer Biol. Med. 2013;10:92–98. doi: 10.7497/j.issn.2095-3941.2013.02.005.
    1. Bakhshi S., Padmanjali K.S., Arya L.S. Infections in childhood acute lymphoblastic leukemia: An analysis of 222 febrile neutropenic episodes. Pediatr. Hematol. Oncol. 2008;25:385–392. doi: 10.1080/08880010802106564.
    1. Kantarjian H., Stein A., Gökbuget N., Fielding A.K., Schuh A.C., Ribera J.M., Wei A., Dombret H., Foà R., Bassan R., et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N. Engl. J. Med. 2017;376:836–847. doi: 10.1056/NEJMoa1609783.
    1. Brown P.A., Ji L., Xu X., Devidas M., Hogan L.E., Borowitz M.J., Raetz E.A., Zugmaier G., Sharon E., Bernhardt M.B., et al. Effect of postreinduction therapy consolidation with blinatumomab vs chemotherapy on disease-free survival in children, adolescents, and young adults with first relapse of B-Cell acute lymphoblastic leukemia: A randomized clinical trial. JAMA. 2021;325:833–842. doi: 10.1001/jama.2021.0669.
    1. O’Brien S., Thomas D.A., Ravandi F., Faderl S., Pierce S., Kantarjian H. Results of the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen in elderly patients with acute lymphocytic leukemia. Cancer. 2008;113:2097–2101. doi: 10.1002/cncr.23819.
    1. Kantarjian H., Thomas D., Jorgensen J., Kebriaei P., Jabbour E., Rytting M., York S., Ravandi F., Garris R., Kwari M., et al. Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. Cancer. 2013;119:2728–2736. doi: 10.1002/cncr.28136.
    1. Jabbour E., Gökbuget N., Advani A., Stelljes M., Stock W., Liedtke M., Martinelli G., O’Brien S., Wang T., Laird A.D., et al. Impact of minimal residual disease status in patients with relapsed/refractory acute lymphoblastic leukemia treated with inotuzumab ozogamicin in the phase III INO-VATE trial. Leuk. Res. 2020;88:106283. doi: 10.1016/j.leukres.2019.106283.
    1. Paul S., Rausch C.R., Jain N., Kadia T., Ravandi F., DiNardo C.D., Welch M.A., Dabaja B.S., Daver N., Garcia-Manero G., et al. Treating leukemia in the time of COVID-19. Acta Haematol. 2020;144:1–13. doi: 10.1159/000508199.
    1. Patel R., Park J., Shah A., Saif M.W. COVID-19 and cancer patients. Cancer Med. J. 2020;3:40–48.
    1. Ribera J.-M., Morgades M., Coll R., Barba P., López-Lorenzo J.-L., Montesinos P., Foncillas M.-A., Cabrero M., Gómez-Centurión I., Morales M.-D., et al. Frequency, clinical characteristics and outcome of adults with acute lymphoblastic leukemia and COVID 19 infection in the first vs. second pandemic wave in Spain. Clin. Lymphoma Myeloma Leuk. 2021;21:e801–e809. doi: 10.1016/j.clml.2021.06.024.
    1. Bargou R., Leo E., Zugmaier G., Klinger M., Goebeler M., Knop S., Noppeney R., Viardot A., Hess G., Schuler M., et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science. 2008;321:974–977. doi: 10.1126/science.1158545.
    1. Hoffmann P., Hofmeister R., Brischwein K., Brandl C., Crommer S., Bargou R., Itin C., Prang N., Baeuerle P.A. Serial killing of tumor cells by cytotoxic T cells redirected with a CD19-/CD3-bispecific single-chain antibody construct. Int. J. Cancer. 2005;115:98–104. doi: 10.1002/ijc.20908.
    1. Gökbuget N., Dombret H., Bonifacio M., Reichle A., Graux C., Faul C., Diedrich H., Topp M.S., Brüggemann M., Horst H.A., et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131:1522–1531. doi: 10.1182/blood-2017-08-798322.
    1. Locatelli F., Zugmaier G., Mergen N., Bader P., Jeha S., Schlegel P.G., Bourquin J.P., Handgretinger R., Brethon B., Rossig C., et al. Blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia: Results of the RIALTO trial, an expanded access study. Blood Cancer J. 2020;10:77. doi: 10.1038/s41408-020-00342-x.
    1. Locatelli F., Zugmaier G., Rizzari C., Morris J.D., Gruhn B., Klingebiel T., Parasole R., Linderkamp C., Flotho C., Petit A., et al. Effect of blinatumomab vs chemotherapy on event-free survival among children with high-risk first-relapse B-Cell acute lymphoblastic leukemia: A randomized clinical trial. JAMA. 2021;325:843–854. doi: 10.1001/jama.2021.0987.
    1. Franquiz M.J., Short N.J. Blinatumomab for the treatment of adult B-cell acute lymphoblastic leukemia: Toward a new era of targeted immunotherapy. Biologics. 2020;14:23–34. doi: 10.2147/BTT.S202746.
    1. Mouttet B., Vinti L., Ancliff P., Bodmer N., Brethon B., Cario G., Chen-Santel C., Elitzur S., Hazar V., Kunz J., et al. Durable remissions in TCF3-HLF positive acute lymphoblastic leukemia with blinatumomab and stem cell transplantation. Haematologica. 2019;104:e244–e247. doi: 10.3324/haematol.2018.210104.
    1. Martinelli G., Boissel N., Chevallier P., Ottmann O., Gökbuget N., Topp M.S., Fielding A.K., Rambaldi A., Ritchie E.K., Papayannidis C., et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia Chromosome-positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: Results from a phase II, single-arm, multicenter study. J. Clin. Oncol. 2017;35:1795–1802. doi: 10.1200/JCO.2016.69.3531.
    1. Maxwell M.B., Maher K.E. Chemotherapy-induced myelosuppression. Semin. Oncol. Nurs. 1992;8:113–123. doi: 10.1016/0749-2081(92)90027-Z.
    1. Klinger M., Brandl C., Zugmaier G., Hijazi Y., Bargou R.C., Topp M.S., Gökbuget N., Neumann S., Goebeler M., Viardot A., et al. Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab. Blood. 2012;119:6226–6233. doi: 10.1182/blood-2012-01-400515.
    1. Mansson R., Zandi S., Anderson K., Martensson I.-L., Jacobsen S.E.W., Bryder D., Sigvardsson M. B-lineage commitment prior to surface expression of B220 and CD19 on hematopoietic progenitor cells. Blood. 2008;112:1048–1055. doi: 10.1182/blood-2007-11-125385.
    1. Wang K., Wei G., Liu D. CD19: A biomarker for B cell development, lymphoma diagnosis and therapy. Exp. Hematol. Oncol. 2012;1:36. doi: 10.1186/2162-3619-1-36.
    1. Kantarjian H.M., DeAngelo D.J., Stelljes M., Martinelli G., Liedtke M., Stock W., Gökbuget N., O’Brien S., Wang K., Wang T., et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N. Engl. J. Med. 2016;375:740–753. doi: 10.1056/NEJMoa1509277.
    1. Kebriaei P., Cutler C., de Lima M., Giralt S., Lee S.J., Marks D., Merchant A., Stock W., van Besien K., Stelljes M. Management of important adverse events associated with inotuzumab ozogamicin: Expert panel review. Bone Marrow Transpl. 2018;53:449–456. doi: 10.1038/s41409-017-0019-y.
    1. Toor S.M., Saleh R., Nair V.S., Taha R.Z., Elkord E. T-cell responses and therapies against SARS-CoV-2 infection. Immunology. 2021;162:30–43. doi: 10.1111/imm.13262.
    1. Shrotri M., van Schalkwyk M.C.I., Post N., Eddy D., Huntley C., Leeman D., Rigby S., Williams S.V., Bermingham W.H., Kellam P., et al. T cell response to SARS-CoV-2 infection in humans: A systematic review. PLoS ONE. 2021;16:e0245532. doi: 10.1371/journal.pone.0245532.
    1. Chandrashekar A., Liu J., Martinot A.J., McMahan K., Mercado N.B., Peter L., Tostanoski L.H., Yu J., Maliga Z., Nekorchuk M., et al. SARS-CoV-2 infection protects against rechallenge in rhesus macaques. Science. 2020;369:812–817. doi: 10.1126/science.abc4776.
    1. Sherina N., Piralla A., Du L., Wan H., Kumagai-Braesch M., Andréll J., Braesch-Andersen S., Cassaniti I., Percivalle E., Sarasini A., et al. Persistence of SARS-CoV-2-specific B and T cell responses in convalescent COVID-19 patients 6–8 months after the infection. Medicine. 2021;2:281–295. doi: 10.1016/j.medj.2021.02.001.
    1. Ogega C.O., Skinner N.E., Blair P.W., Park H.S., Littlefield K., Ganesan A., Dhakal S., Ladiwala P., Antar A.A., Ray S.C., et al. Durable SARS-CoV-2 B cell immunity after mild or severe disease. J. Clin. Investig. 2021;131:e145516. doi: 10.1172/JCI145516.
    1. Quast I., Tarlinton D. B cell memory: Understanding COVID-19. Immunity. 2021;54:205–210. doi: 10.1016/j.immuni.2021.01.014.
    1. Mato A.R., Roeker L.E., Lamanna N., Allan J.N., Leslie L., Pagel J.M., Patel K., Osterborg A., Wojenski D., Kamdar M., et al. Outcomes of COVID-19 in patients with CLL: A multicenter international experience. Blood. 2020;136:1134–1143. doi: 10.1182/blood.2020006965.
    1. Gesiotto Q., Cheema A., Avaiya K., Shah B., Greene J. COVID-19 virus infection in three patients with hypogammaglobulinemia. Cureus. 2021;13:e15256. doi: 10.7759/cureus.15256.
    1. Zugmaier G., Topp M.S., Alekar S., Viardot A., Horst H.A., Neumann S., Stelljes M., Bargou R.C., Goebeler M., Wessiepe D., et al. Long-term follow-up of serum immunoglobulin levels in blinatumomab-treated patients with minimal residual disease-positive B-precursor acute lymphoblastic leukemia. Blood Cancer J. 2014;4:244. doi: 10.1038/bcj.2014.64.
    1. Doan A., Pulsipher M.A. Hypogammaglobulinemia due to CAR T-cell therapy. Pediatr. Blood Cancer. 2018;65 doi: 10.1002/pbc.26914.
    1. Hill J.A., Seo S.K. How I prevent infections in patients receiving CD19-targeted chimeric antigen receptor T cells for B-cell malignancies. Blood. 2020;136:925–935. doi: 10.1182/blood.2019004000.

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