Gemtuzumab ozogamicin (Mylotarg)

General information

Class/mechanism: Antibody-cytotoxic agent conjugate. Gemtuzumab ozogamicin is comprised of a recombinant humanized IgG4 kappa antibody against CD33--an adhesion protein expressed on the surface of leukemic blasts and immature normal cells of myelomonocytic lineage, but not on normal hematopoietic stem cells--conjugated with a cytotoxic agent, calicheamicin. The antibody-cytotoxic agent is internalized after binding, and the calicheamicin derivative binds to DNA in the minor groove, causing DNA double strand breaks and cell death.
Route: IV
Extravasation: no information

For conciseness and simplicity, HemOnc.org currently will focus on treatment regimens and not list information such as: renal/hepatic dose adjustments, metabolism (including CYP450), excretion, monitoring parameters (although this will be considered for checklists), or manufacturer. Instead, for the most current information, please refer to your preferred pharmacopeias such as Micromedex, Lexicomp, UpToDate (courtesy of Lexicomp), or the prescribing information.

Diseases for which it is used

Gemtuzumab ozogamicin is currently withdrawn from the market so these references are for historical purposes, only. If the drug is re-introduced these will be moved back to active page(s).

• Acute myeloid leukemia

References

1. Sievers EL, Larson RA, Stadtmauer EA, Estey E, Löwenberg B, Dombret H, Karanes C, Theobald M, Bennett JM, Sherman ML, Berger MS, Eten CB, Loken MR, van Dongen JJ, Bernstein ID, Appelbaum FR; Mylotarg Study Group. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol. 2001 Jul 1;19(13):3244-54. link to original article PubMed
2. Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J, Larson RA, Erba HP, Stiff PJ, Stuart RK, Walter RB, Tallman MS, Stenke L, Appelbaum FR. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013 Jun 13;121(24):4854-60. Epub 2013 Apr 16. link to original article PubMed
3. Abstract: Meta-analysis: Stephen Petersdorf, Elihu H. Estey, Megan Othus, Frederick R. Appelbaum, Sylvie Castaigne, Herve Dombret, Sylvie Chevret, Jacques Delaunay, Norbert Ifrah, Jean-Yves Cahn, Christian Recher, Alan K Burnett. The Addition Of Gemtuzumab Ozogamicin (GO) To Induction Chemotherapy Reduces Relapse and Improves Survival In Patients Without Adverse Risk Karyotype: Results Of An Individual Patient Meta-Analysis Of The Five Randomised Trials. Blood Nov 2013,122(21)356 link to original abstract
4. Amadori S, Suciu S, Selleslag D, Aversa F, Gaidano G, Musso M, Annino L, Venditti A, Voso MT, Mazzone C, Magro D, De Fabritiis P, Muus P, Alimena G, Mancini M, Hagemeijer A, Paoloni F, Vignetti M, Fazi P, Meert L, Ramadan SM, Willemze R, de Witte T, Baron F. 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 Mar 20;34(9):972-9. Epub 2016 Jan 25. link to original article PubMed
5. GO-A-HAM: Hütter-Krönke ML, Benner A, Döhner K, Krauter J, Weber D, Moessner M, Köhne CH, Horst HA, Schmidt-Wolf IG, Rummel M, Götze K, Koller E, Petzer AL, Salwender H, Fiedler W, Kirchen H, Haase D, Kremers S, Theobald M, Matzdorff AC, Ganser A, Döhner H, Schlenk RF. Salvage therapy with high-dose cytarabine and mitoxantrone in combination with all-trans retinoic acid and gemtuzumab ozogamicin in acute myeloid leukemia refractory to first induction therapy. Haematologica. 2016 Apr 1. [Epub ahead of print] link to original article PubMed

Azacitidine & Gemtuzumab ozogamicin

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Regimen

Study	Evidence
Nand et al. 2008	Phase II
Nand et al. 2013	Phase II

Patients with WBC > 10k at presentation were pre-treated with Hydrea. Leukapheresis was recommended for patients with WBC > 100k. Nand et al. 2008 did not describe the maintenance portion of the regimen, and used only SC azacitidine.

Pre-treatment phase

• Hydroxyurea (Hydrea) 1500 mg PO twice per day or "in higher doses if necessary"

Once WBC is less than 10k, stop Hydrea and proceed:

Induction

• Azacitidine (Vidaza) 75 mg/m2 SC or IV once per day on days 1 to 7
• Gemtuzumab ozogamicin (Mylotarg) 3 mg/m2 IV once on day 8

Supportive medications:

• "Appropriate premedications" which were not specified, for Gemtuzumab ozogamicin (Mylotarg)

If D14 bone marrow with ≥5% blasts, a second induction cycle identical to the first was administered. Patients achieving CR or CRi were to receive azacitidine and gemtuzumab ozogamicin consolidation within 60 days.

References

1. Nand S, Godwin J, Smith S, Barton K, Michaelis L, Alkan S, Veerappan R, Rychlik K, Germano E, Stiff P. Hydroxyurea, azacitidine and gemtuzumab ozogamicin therapy in patients with previously untreated non-M3 acute myeloid leukemia and high-risk myelodysplastic syndromes in the elderly: results from a pilot trial. Leuk Lymphoma. 2008 Nov;49(11):2141-7. link to original article contains verified protocol PubMed
2. Nand S, Othus M, Godwin JE, Willman CL, Norwood TH, Howard DS, Coutre SE, Erba HP, Appelbaum FR. A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia. Blood. 2013 Nov 14;122(20):3432-9. Epub 2013 Oct 3. link to original article contains verified protocol PubMed

Azacitidine & Gemtuzumab ozogamicin

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Regimen

Study	Evidence
Nand et al. 2013	Phase II

Treatment preceded by azacitidine and gemtuzumab ozogamicin induction.

• Azacitidine (Vidaza) 75 mg/m2 SC or IV once per day on days 1 to 7
• Gemtuzumab ozogamicin (Mylotarg) 3 mg/m2 IV once on day 8

Supportive medications:

• "Appropriate premedications" which were not specified, for Gemtuzumab ozogamicin (Mylotarg)
• Growth factors per physician discretion

1 cycle

Patients were to start azacitidine maintenance within 42 days of completion of consolidation.

References

1. Nand S, Othus M, Godwin JE, Willman CL, Norwood TH, Howard DS, Coutre SE, Erba HP, Appelbaum FR. A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia. Blood. 2013 Nov 14;122(20):3432-9. Epub 2013 Oct 3. link to original article contains verified protocol PubMed

Azacitidine, Gemtuzumab & Vorinostat

Regimen, Walter et al. 2013

Phase I/II

This is the MTD used in the phase II portion, which was tested on 43 patients.

• Azacitidine (Vidaza) 75 mg/m2 SC or IV once per day on days 1 to 7
• Gemtuzumab ozogamicin (Mylotarg) 3 mg/m2 IV once on days 4 & 8
• Vorinostat (Zolinza) 400 mg PO once per day on days 1 to 9

Up to 6 cycles based on response; cycle length not specified beyond 2nd cycle

References

1. Walter RB, Medeiros BC, Gardner KM, Orlowski KF, Gallegos L, Scott BL, Hendrie PC, Estey EH. Gemtuzumab ozogamicin in combination with vorinostat and azacitidine in older patients with relapsed or refractory acute myeloid leukemia: a phase 1/2 study. Haematologica. 2013 Oct 18. [Epub ahead of print] link to original article contains verified protocol PubMed

• Acute promyelocytic leukemia

Patient drug information

• Gemtuzumab ozogamicin (Mylotarg) patient drug information (Chemocare)

History of changes in FDA indication

• 5/17/2000: Granted FDA accelerated approval for the treatment of patients with CD33 positive acute myeloid leukemia in first relapse who are 60 years of age or older and who are not considered candidates for cytotoxic chemotherapy.
• 10/15/2010: Withdrawn from US market, but there are ongoing investigations regarding reintroduction into the US.