Efficacy, Safety, and Tolerance of Gemtuzumab Ozogamicin Combined with FLAG/FLAG-Ida or Azacitidine in Relapsed/Refractory Acute Myeloblastic Leukemia

IG Budaeva, DV Zaitsev, AA Shatilova, EN Tochenaya, AV Petrov, RI Vabishchevich, DV Motorin, RSh Badaev, DB Zammoeva, VV Ivanov, SV Efremova, KV Bogdanov, YuV Mirolyubova, TS Nikulina, YuA Alekseeva, AYu Zaritskey, LL Girshova

VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

For correspondence: Irina Garmaevna Budaeva, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel.: +7(931)351-07-06; e-mail: irina2005179@mail.ru

For citation: Budaeva IG, Zaitsev DV, Shatilova AA, et al. Efficacy, Safety, and Tolerance of Gemtuzumab Ozogamicin Combined with FLAG/FLAG-Ida or Azacitidine in Relapsed/Refractory Acute Myeloblastic Leukemia. Clinical oncohematology. 2021;14(3):299–307. (In Russ).

DOI: 10.21320/2500-2139-2021-14-3-299-307


Aim. To assess the efficacy, safety, and tolerance of gemtuzumab ozogamicin (GO) combined with FLAG/FLAG-Ida chemotherapy or azacitidine in patients with relapsed/refractory acute myeloblastic leukemia (AML) in clinical practice.

Materials & Methods. The study included 32 patients (16 men and 16 women). The median age was 44 years (range 23–83 years). Among them there were 15 (46.8 %) patients with refractory and 17 (53.2 %) patients with relapsed AML. GO combined with FLAG/FLAG-Ida was administered to 15 (46.8 %) patients, whereas 17 (53.2 %) patients were treated with GO and azacitidine combination. Therapy safety was assessed according to CTCAE v. 5.0.

Results. Overall response rate including complete remission (CR), CR MRD–, CR with incomplete hematologic recovery, and morphologic leukemia-free status was 59.4 % (19/32). Refractoriness was observed in 31.25 % (10/32) of patients. Early mortality was 9.4 % (3/32). Overall response was 64.7 % (11/17) in the azacitidine and 53.3 % (8/15) in the FLAG/FLAG-Ida groups. In 4 (80 %) out of 5 patients with prior to FLAG treatment refractoriness, the response was achieved after GO + azacitidine therapy. In 58.9 % (10/17) of patients who received GO + azacitidine therapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be performed. The incidence of GO infusion complications in the tested groups did not significantly differ (= 0.72) and was 46.7 % (7/15) (40 % with grade 1/2 and 6.7 % with grade 3) in the GO + FLAG/FLAG-Ida group and 35.3 % (6/17) (29.4 % with grade 1/2 and 5.9 % with grade 4) in the GO + azacitidine group. In the GO + FLAG/FLAG-Ida group 5 (33.3 %) patients experienced serious adverse events (SAE) of sepsis. In the GO + azacitidine group SAEs were reported in 6 (35.3 %) patients: 4 (66.6 %) with sepsis, 1 (16.7 %) with acute cardiovascular failure, and 1 (16.7 %) with acute respiratory failure. The median (range) duration was 23 (10–39) days for neutropenia grade 4, 24 (11–38) days for neutropenia grade 3, 21 (11–41) days for thrombocytopenia grade 4, 26 (16–45) days for thrombocytopenia grade 3, and 25 (22–45) days for thrombocytopenia grade 1/2. Thrombocytopenia duration was longer in patients with GO + FLAG/FLAG-Ida therapy, however, no significant differences were identified. No cases of veno-occlusive liver disease were reported. Median overall survival (OS) for both groups (n = 32) was 31.4 months, median disease-free survival (n = 21) was 13.3 months. In the group of patients with effective treatment, the median OS was not reached. In non-responders, it was 18 months (= 0.0442).

Conclusion. GO combined with FLAG/FLAG-Ida chemotherapy or azacitidine proved effective in relapsed/refractory AML patients. Remission did not appear to be associated with ELN risk, gender, age, CD33 expression, number of prior therapy lines, or number of relapses. GO + azacitidine combination showed efficacy, safety, and good tolerance in patients with prior high-dose chemotherapy refractoriness as well as low ECOG performance status. That allowed for the subsequent allo-HSCT administration to these patients. There was no significant difference between the groups of patients in the incidence of hematologic, non-hematologic toxicity, and time to hematologic recovery. Thrombocytopenia duration was longer in patients with GO + FLAG/FLAG-Ida therapy which is consistent with literature data. GO-based effective treatment in relapsed/refractory AML considerably improves OS: during 36 months of follow-up the median was not reached.

Keywords: acute myeloblastic leukemia, relapse, refractoriness, gemtuzumab ozogamicin, FLAG/FLAG-Ida regimens, azacitidine, efficacy, safety, toxicity.

Received: February 5, 2021

Accepted: May 15, 2021

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  1. Wang ES, Aplenc R, Chirnomas D, et al. Safety of gemtuzumab ozogamicin as monotherapy or combination therapy in an expanded-access protocol for patients with relapsed or refractory acute myeloid leukemia. Leuk Lymphoma. 2020;61(12):1965–2973. doi: 10.1080/10428194.2020.1742897.
  2. Dombret H, Gardin C. An update of current treatments for adult acute myeloid leukemia. Blood. 2016;127(1):53–61. doi: 10.1182/blood-2015-08-604520.
  3. Kouchkovsky I, Abdul-Hay M. Acute myeloid leukemia: a comprehensive review and 2016 update. Blood Cancer J. 2016;6(7):e441. doi: 10.1038/bcj.2016.50.
  4. Sievers EL, Larson RA, Stadtmauer EA, et al. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol. 2001;19(13):3244–54. doi: 10.1200/JCO.2001.19.13.3244.
  5. Zein N, Poncin M, Nilakantan R, et al. Calicheamicin gamma 1I and DNA: molecular recognition process responsible for site-specificity. Science. 1989;244(4905):697–9. doi: 10.1126/science.2717946.
  6. Linenberger ML. CD33-directed therapy with gemtuzumab ozogamicin in acute myeloid leukemia: progress in understanding cytotoxicity and potential mechanisms of drug resistance. Leukemia. 2005;19(2):176–82. doi: 10.1038/sj.leu.2403598.
  7. Sievers EL, Appelbaum FR, Spielberger RT, et al. Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: A phase I study of an anti-CD33 calicheamicin immunoconjugate. Blood. 1999;93(11):3678–84. doi: 10.1182/blood.v93.11.3678.411k24_3678_3684.
  8. Bross PF, Beitz J, Chen G, et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res. 2001;7(6):1490–6.
  9. Deangelo DJ, Liu D, Stone R, et al. Preliminary report of a phase 2 study of gemtuzumab ozogamicin in combination with cytarabine and daunorubicin in patients < 60 years of age with de novo acute myeloid leukemia. Proceed Am Soc Clin Oncol. 2003: Abstract 2325.
  10. Petersdorf SH, Kopecky KJ, et al. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013;121(24):4854–60. doi: 10.1182/blood-2013-01-466706.
  11. Caron PC, Jurcic JG, Scott AM, et al. A phase 1B trial of humanized monoclonal antibody M195 (anti-CD33) in myeloid leukemia: specific targeting without immunogenicity. Blood. 1994;83(7):1760–8. doi: 10.1182/blood.v83.7.1760.bloodjournal8371760.
  12. Castaigne S, Pautas C, Terre C, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012;379(9825):1508–16. doi: 10.1016/S0140-6736(12)60485-1.
  13. Lambert J, Pautas С. Terre Ch, et al. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019;104(1):113–9. doi: 10.3324/haematol.2018.188888.
  14. Amadori S, Suciu S, Selleslag D, et al. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol. 2016;34(9):972–9. doi: 10.1200/jco.2015.64.0060.
  15. Taksin AL, Legrand O, Raffoux E, et al. High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the alfa group. Leukemia. 2007;21(1):66–71. doi: 10.1038/sj.leu.2404434.
  16. Debureaux P-E, Labopin М, Mamez A-C, et al. Fractionated gemtuzumab ozogamicin in association with high dose chemotherapy: a bridge to allogeneic stem cell transplantation in refractory and relapsed acute myeloid leukemia. Bone Marrow Transplant. 2019;55(2):452–60. doi: 10.1038/s41409-019-0690-2.
  17. Chevallier P, Delaunay J, Turlure P, et al. Long-term disease-free survival after gemtuzumab, intermediate-dose cytarabine, and mitoxantrone in patients with CD33(+) primary resistant or relapsed acute myeloid leukemia. J Clin Oncol. 2008;26(32):5192–7. doi: 10.1200/jco.2007.15.9764.
  18. Medeiros BC, Tanaka TN, Balaian L, et al. A Phase I/II Trial of the Combination Azacitidine and Gemtuzumab Ozogamicin for Treatment of Relapsed Acute Myeloid Leukemia. Clin Lymphoma Myel Leuk. 2018;18(5):346–352.e5. doi: 10.1016/j.clml.2018.02.017.
  19. Walter RB, Medeiros BC, Gardner KM, et al. Gemtuzumab ozogamicin in combination with vorinostat and azacitidine in older patients with relapsed or refractory acute myeloid leukemia: a phase I/II study. Haematologica. 2013;99(1):54–9. doi: 10.3324/haematol.2013.096545.
  20. Arain S, Christian S, Patel PR. Safety and efficacy of gemtuzumab ozogamicin and venetoclax in patients with relapsed or refractory CD33+ acute myeloid leukemia: A phase Ib study. J Clin Oncol. 2020;38(15_suppl):TPS7566. doi: 10.1200/JCO.2020.38.15_suppl.TPS7566.
  21. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. 2016;127(20):2391–405. doi: 10.1182/blood-2016-03-643544.
  22. Dohner H, Elihu H, Estey EH, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3):453–74. doi: 10.1182/blood-2009-07-235358.
  23. Зайцев Д.В., Гиршова Л.Л., Иванов В.В. и др. Гемтузумаб озогамицин в лечении пациентов с рефрактерным течением острого миелоидного лейкоза, находящихся в критическом состоянии (описание 3 клинических наблюдений). Клиническая онкогематология. 2020;13(1):67–74. doi: 10.21320/2500-2139-2020-13-1-67-74.
    [Zaitsev DV, Girshova LL, Ivanov VV, et al. Gemtuzumab Ozogamicin in the Treatment of Critical Patients with Refractory Acute Myeloid Leukemia (3 Case Reports). Clinical oncohematology. 2020;13(1):67–74. doi: 10.21320/2500-2139-2020-13-1-67-74. (In Russ)]
  24. Stone RM, Moser B, Sanford B, et al. High dose cytarabine plus gemtuzumab ozogamicin for patients with relapsed or refractory acute myeloid leukaemia: Cancer and Leukaemia Group B study 19902. Leuk Res. 2011;35(3):329–33. doi: 10.1016/j.leukres.2010.07.017.
  25. Hosono N, Ookura M, Araie H, et al. Clinical outcomes of gemtuzumab ozogamicin for relapsed acute myeloid leukemia: single-institution experience. Int J Hematol. 2020;113(3):362–9. doi: 10.1007/s12185-020-03023-4.
  26. Будаева И.Г., Гиршова Л.Л., Овсянникова Е.Г. и др. Прогнозирование эффективности режима FLAG ± Ida у пациентов с рецидивами и рефрактерным течением острых миелоидных лейкозов. Клиническая онкогематология. 2019;12(3):289–96. doi: 10.21320/2500-2139-2019-12-3-289-296.
    [Budaeva IG, Girshova LL, Ovsyannikova EG, et al. Prediction of FLAG ± Ida Regimen Efficacy in Patients with Relapsed/Refractory Acute Myeloid Leukemia. Clinical oncohematology. 2019;12(3):289–96. doi: 10.21320/2500-2139-2019-12-3-289-296. (In Russ)]
  27. Chantepie SP, Reboursiere E, Mear JB, et al. Gemtuzumab ozogamicin in combination with intensive chemotherapy in relapsed or refractory acute myeloid leukemia. Leuk Lymphoma. 2015;56(8):2326–30. doi: 3109/10428194.2014.986478.
  28. Burnett AK, Russell NH, Hills RK, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012;30(32):3924–31. doi: 10.1200/jco.2012.42.2964.