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Differentiation Induction in Acute Promyelocytic Leukemia
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
The treatment of APL has evolved rapidly over the last 15 years. Once a disease with poor OS and often an abrupt catastrophic course, APL has become the most curable of all the subtypes of AML. The unique biology of APL, in which an aberrant fusion protein inhibits differentiation and apoptosis, lends itself to a therapeutic strategy that overcomes the transcription block. ATRA and ATO both target the fusion protein and restore differentiation and apoptosis by degrading the PML-RARα fusion protein. Both agents induce a high rate of remission as single agents. Synergy between ATRA and ATO may permit a reduction or possibly elimination of chemotherapy in most patients. This approach could be used in conjunction with gemtuzumab ozogamicin for induction and potentially offer patients with a curative approach without the use of standard intensive chemotherapy. The role of other novel agents such as FLT3 inhibitors, monoclonal antibodies, antiangiogenesis agents, differentiation agents, and histone deacetylase inhibitors remains to be determined. Insights gained in the molecular events that lead to APL may potentially provide advances in the understanding of leukemogenesis in other AML subtypes. These may lead to the development of other differentiation-inducing therapies or novel strategies for other AML subtypes.
Specific Therapy for Leukemias
Published in Tariq I Mughal, John M Goldman, Sabena T Mughal, Understanding Leukemias, Lymphomas, and Myelomas, 2017
Tariq I Mughal, John M Goldman, Sabena T Mughal
Gemtuzumab ozogamicin (Mylotarg; GO) is a novel agent which comprises a humanized monoclonal antibody directed against the CD33 molecule expressed on the surface of leukemia blasts in over 90% of patients with AML linked to calicheamycin, a very potent cell toxin. Gemtuzumab has been reported to have a few potentially serious side-effects and patients need to be observed carefully as we gain further experience. In the initial studies, there was a high incidence of infusion-related symptoms, such as skin rashes, cough, breathing difficulties, fevers, and low blood pressure; all of these effects were fully reversible. It is also associated with liver toxicity, resembling veno-occlusive disease, which is usually seen after a stem cell transplant (SCT).
Pulmonary reactions to novel chemotherapeutic agents and biomolecules
Published in Philippe Camus, Edward C Rosenow, Drug-induced and Iatrogenic Respiratory Disease, 2010
Gemtuzumab ozogamicin is a humanized anti-CD33 monoclonal antibody linked to a semisynthetic derivative of cali-cheamicin, a cytotoxic antibiotic. Its primary indication is for patients with CD33 positive acute myeloid leukaemia (AML) in first relapse who are 60 years of age or older and who are not candidates for other cytotoxic chemotherapy. Pre-approval testing identified dyspnoea and transient hypoxaemia as pulmonary adverse reactions, but more serious respiratory events were observed in post-marketing safety data.103 During the first 6 months after approval, there were eight patients who experienced pulmonary events immediately after or within 24 hours of administration of the drug. Of these events, five were ARDS, and three were reported as ‘pulmonary oedema’. Six of the patients had pre-treatment leucocyte counts greater than 60 000/µ L. Although pulmonary leucostasis can have a similar clinical presentation in patients with very high blast counts, the temporal association of the events with drug administration suggested a drug reaction. To reduce the risk of severe pulmonary toxicity, the authors of the report recommended reduction in peripheral blast counts to below 30 000/µ L with hydroxyurea or leukapheresis prior to gemtuzumab ozogamicin administration.103
Targeting cancer with antibody-drug conjugates: Promises and challenges
Published in mAbs, 2021
Alexis Q. Dean, Shen Luo, Julianne D. Twomey, Baolin Zhang
In 2017, inotuzumab ozogamicin (Besponsa®), a Pfizer product, was approved for treatment in adults with relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia. The ADC targets the CD22 surface marker using an IgG4 to deliver approximately 6 calicheamicin molecules. The payload is conjugated via surface-exposed lysines using an acid-labile linker.4 This design nearly mirrors that of gemtuzumab ozogamicin (Mylotarg®), an anti-CD33 ADC with an average of 2–3 calicheamicin payloads conjugated to the antibody. Gemtuzumab ozogamicin was the first ADC to receive accelerated approval in 2000, contingent on fulfilling the post-marketing requirement of a randomized trial to confirm clinical benefit (S0106; NCT00085709) (Figure 2a).5,6 However, the trial did not confirm the clinical benefit but instead raised safety concerns due to an increase in treatment-related fatalities compared to the control group receiving standard chemotherapy. The leading causes of fatality in the treatment arm were associated with infection and hemorrhage. Ultimately, the results of the trial led to the voluntary withdrawal of the application by Pfizer in 2010.7,8 Following modifications to the dosing schedule, which was associated with decreased incidence of hepatotoxicity and early mortality, and to address the critical unmet need for acute myeloid leukemia patients, gemtuzumab ozogamicin was granted approval again in 2017.9
Current and emerging treatments for acute promyelocytic leukemia
Published in Expert Opinion on Orphan Drugs, 2019
Musa Yilmaz, Kiran Naqvi, Farhad Ravandi
Introduction of ATO into APL therapy has changed the treatment landscape and allowed development of chemotherapy-free regimen with high success rates. Every patient with suspected APL should start on ATRA 45 mg/m2/day in two divided doses, and ATO 0.15 mg/kg/day should be added upon confirmation of the diagnosis. General consensus is that patients should be on ATRA + ATO until CR. However, clinicians should have a low threshold to hold one or both of these agents in cases of severe differentiation syndrome, or in patients fluid overload who respond diuretics poorly. ATRA and ATO can be resumed when symptoms resolved. Patients with high-risk APL (WBC >10 K) should receive one dose of gemtuzumab ozogamicin early during induction, perhaps within the first 5 days. Gemtuzumab can be given at a dose of 9 mg/m2 as published by MD Anderson group [27] or at 6 mg/m2 dose as used effectively by the United Kingdom group [29]. If gemtuzumab is not available immediately, idarubicin is a great alternative, which can be given at 12 mg/m2 to control leukocytosis. Additional doses of idarubicin (6 mg/m2) may be used in patients with worsening leukocytosis despite the initial dose. Occasionally, patients with low-risk APL can develop leukocytosis during therapy. In such cases, we recommend use of gemtuzumab or idarubicin whenever WBC rises above 10,000/µL.
Long-term delivery of protein and peptide therapeutics for cancer therapies
Published in Expert Opinion on Drug Delivery, 2019
Sadia Sikder, Vrinda Gote, Meshal Alshamrani, Jeff Sicotte, Dhananjay Pal
In the past two decades, more than 60 ADCs have entered the clinical trials but the US FDA has approved only four. Gemtuzumab ozogamicin (Mylotarg®) was the first approved ADC in 2001 as intravenous injection for treatment of myelogenous leukemia (AML). Mylotarg® was withdrawn 10 years later when it was appeared to be linked to sinusoidal obstruction syndrome (SOS), which causes fatal liver damage. Gemtuzumab ozogamicin was modified with a fractionated dose of ozogamicin to reduce the hepatotoxic side effects of the original dose. Recently in September 2017, US FDA announced the approval of Mylotarg® for treatment of acute AML in newly diagnosed in adult population, whose tumors express the CD33 antigen (CD33-positive AML) [51]. Apart from Mylotarg® the other US FDA approved intravenous ADCs are brentuximab vedotin (Adcetris®), trastuzumab emtansine (Kadcyla®) and inotuzumab ozogamicin (Besponsa®). Adcetris® is approved for the treatment of systemic anaplastic large cell lymphoma and CD30+ Hodgkin lymphoma. Kadcyla® targets human epidermal growth factor 2 (HER2)+ and is indicated for HER2+ metastatic breast cancer and Besponsa® is approved for mitigating the effects of CD22+ non-Hodgkin lymphoma [52,53].