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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.
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
Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Inotuzumab ozogamicin (Besponsa™) is an antibody-drug conjugate used to treat relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). It consists of a semisynthetic derivative of N-acetyl ɣ-calicheamicin 1, 2-dimethyl hydrazine dichloride (NAc ɣ-calicheamicin DMH), a potent DNA-cleaving agent, covalently linked via an acid-labile 4-(4′-acetylphenoxy) butanoic acid (acetyl butyrate) linker to a humanized monoclonal IgG4 antibody, G544 (Figure 7.33). The linker provides stability at physiologic pH but successfully releases the calicheamicin inside the acidic environment of the lysosomes. Inotuzumab ozogamicin was made through a collaboration by researchers from Celltech and Wyeth, but developed by Pfizer after it acquired Wyeth. Structure of inotuzumab ozogamicin (BesponsaTM) which has an average loading of 5–7 moles of ɣ-calicheamicin payload per mole of antibody (Image from Jani, Darshana & Nowak, John & Chen, Ying & Boni, Joseph & Gorovits, Boris. (2018). Assessment of clinical immunogenicity of inotuzumab ozogamicin in patients with non-Hodgkin lymphoma and acute lymphoblastic leukemia. AAPS Open. 4. 10.1186/s41120-018-0021-5).
Factors Affecting the Cancer Immunotherapeutic Efficacy of T Cell Bispecific Antibodies and Strategies for Improvement
Published in Immunological Investigations, 2022
Meixiao Long, Alice S. Mims, Zihai Li
For some malignancies, targeted therapy or immunotherapy could provide an alternative approach to achieve significant debulking and even remission with minimal negative impact on T-cell number and function. Inotuzumab ozogamicin is an antibody‒drug conjugate targeting CD22 that is expressed by most acute lymphoblastic leukemia (ALL). Sequential treatment with the single agent inotuzumab followed by blinatumomab has been demonstrated to have good efficacy and safety profiles in clinical trials with ALL patients (Ueda et al. 2022). Similarly, tyrosine kinase inhibitors have been used for prephase debulking for Ph-positive ALL before initiating treatment with blinatumomab in several clinical trials (Advani et al. 2021; Short et al. 2021). For multiple myeloma patients, there are more options for debulking without harming T-cell immunity. CD38 antibodies, proteasome inhibitors and immunomodulatory drugs (IMiDs) are all standard treatment options. Proteosome inhibitors and CD38 antibodies have a much lower impact on T-cell immunity than cytotoxic chemotherapies. IMiDs such as lenalidomide and pomalidomide have been found to enhance the potency of BCMA BsAbs in multiple myeloma preclinical models (Ghobadi et al. 2020). Thus, myeloma patients can achieve significant cytoreduction and even complete remission without significantly compromising T-cell immunity. Currently, there are multiple ongoing clinical trials combining IMiDs and/or proteasome inhibitors with BCMA BsAb.
Treatment and outcome of Philadelphia chromosome-positive acute lymphoblastic leukemia in adults after relapse
Published in Expert Review of Anticancer Therapy, 2020
Marie Balsat, Victoria Cacheux, Martin Carre, Emmanuelle Tavernier-Tardy, Xavier Thomas
CD22 is a 135-kDa sialoglycoprotein that mediates intercellular interactions for sialic-acid bearing ligands and modulates antigen receptor signaling and B-cell activation. CD22 is an important B cell-restricted surface antigen that is expressed in 96% of B cell-lineage ALL [103]. It is rapidly internalized on binding to anti-CD22 making it an attractive target for targeted therapy with chemotherapeutic conjugates. Following the development of gemtuzumab ozogamicin, an anti-CD33 antibody-drug conjugate, in acute myeloid leukemia, inotuzumab ozogamicin, an anti-CD22 antibody-drug conjugate, was developed. Inotuzumab ozogamicin is a humanized MoAb against CD22 conjugated via a bi-functional linker to a potent cytotoxic agent calicheamicin derived from Micromonospora echinospora, which induces DNA double-strand breaks and apoptosis independent of cell cycle progression [104]. Upon binding to CD22 receptors, inotuzumab is rapidly internalized, trafficked through lysosomes leading to hydrolysis of inactive calicheamicin. Calicheamicin is then reduced to its active form by intracellular glutathione. In the nucleus, active calicheamicin binds to DNA and generates free radicals leading to DNA double-strand breaks and cellular apoptosis (Figure 2).
Intravenous arsenic trioxide and all-trans retinoic acid as front-line therapy for low-risk acute promyelocytic leukemia
Published in Expert Review of Hematology, 2019
AML17 is a controlled, randomized, multicenter trial conducted by the NCRI cooperative group that enrolled 235 patients randomized to receive 1:1 ATRA and arsenic trioxide or ATRA and idarubicin. In the ATRA and arsenic trioxide group, arsenic trioxide was given intravenously at 0.3 mg/kg on days 1–5 of each course, and at 0.25 mg/kg twice weekly in weeks 2–8 of course 1 and weeks 2–4 of courses 2–5. High-risk patients received a single dose of gemtuzumab ozogamicin at the dose of 6 mg/mq. The primary endpoint was quality of life and the results showed that it did not differ between the two arms. The CR rate was 94% in the ATO arm vs 89% in the chemotherapy arm. No differences were reported in the 4-year OS (93% vs 89%, respectively), but significant differences were observed in the 4-year molecular recurrence-free survival (98% vs 70%), EFS (91% vs 70%) and cumulative incidence of molecular relapse (0% vs 27%) or morphologic relapse (1% vs 18%). Fifty-seven patients in the ATRA and idarubicin group and 40 patients in the ATRA and arsenic trioxide group reported grade 3–4 toxicities: the most common toxicities observed in the standard arm were alopecia and oral toxicity, whereas in the ATO arm they were represented by an increase in liver enzymes. The results of this trial showed again the feasibility of a non-chemotherapy approach for APL patients, although no differences were reported in terms of quality of life [46] (Table 2).