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Precision medicine in acute myeloid leukemia
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
CD33 antibody-drug conjugates such as gemtuzumab ozogamicin and vadastuximab talirine (SGN-CD33A) (Burnett et al., 2012; Daver et al., 2016; Minagawa et al., 2016; Table 10.9); Hedgehog inhibitors like sonidebig (erismodegib, LDE255), glasdegib (PF-04449913), and vismodegib; neddylation and subsequent ubiquitination inhibitors (pevonedistat); and Wnt signaling pathway inhibitors (Fukushima et al., 2016; Hanna and Shevde, 2016; Ma et al., 2015; Medler et al., 2015; Swords et al., 2017) together with standard chemotherapy are in ongoing trials. Further therapeutic approaches including NF-κB signaling pathway inhibition (Bosman et al., 2016; Fuchs 2010; Siveen et al., 2017; Zhou et al., 2015), PI3 K/AKT/mTOR signaling pathway inhibition, (Brenner et al., 2016; Fuchs 2011; Hauge et al., 2016) and targeting the S100A8/S100A9-TLR4-ERK/JNK/p38 pathway (Laouedj et al., 2017; Tamburini, 2017) were studied. Cell division cycle 25 (CDC25) protein phosphatases inhibition had antiproliferative effects on primary human AML cells for a subset of patients identified by gene expression profiling (Brenner et al., 2017).
Acute Myeloid Leukaemia
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Clofarabine, a novel second-generation deoxynucleoside analogue developed from two other purine analogues, fludarabine and cladribine, has now been in clinical trials for almost two decades. It doubles response rates in older patients with AML but does not improve overall survival, but is not currently licensed; it is, however, licensed for patients with ALL. The results of a recent randomized phase II study of clofrabine-based consolidation, compared with high-dose cytarabine, for patients <60 years of age with AML in first remission, support the use of a clofarabine-based combination as a reasonable post-remission consolidation treatment. This approach appears particularly attractive for patients who are considered for an allo-SCT and a suitable donor is not available or not identified. A similar drug, troxacitabine, is currently in clinical trials. Cloretazine, a novel DNA alkylating agent, is being tested in newly diagnosed older patients with AML. Volasertib, a polo-like kinases (PLK1) inhibitor is being tested in a randomized phase III study, in combination with low-dose cytarabine or decatibine in newly diagnosed older AML patients considered to be unfit for conventional treatment. Several other new (and not so new) agents are at an early stage of development in AML. These include elacytarabine (a cytotoxic nucleoside analogue), tosedostat (an aminopeptidase inhibitor), vosaroxin (a novel topo II anthracycline-like inhibitor), sapacitibine (a novel nucleoside), EPZ-5676 (DOT1L inhibitor), ABT (BCL-2 inhibitors), BET bromodomain inhibitors, vadastuximab talirine (SGN-CD33A), a novel antibody-drug conjugate similar to GO and the next-generation DNA hypomethylating agents, guadecitabine (SGI-110). And based on recent enhanced biological understanding, there is interest in testing BCL2 inhibition, for example, with venetoclax, in combination with standard AML drugs. Indeed, preliminary results of venetoclax in combination with azacytidine, decitabine and cytarbine are encouraging. There is also some interest, though a sound scientific rationale is lacking, of using the ATRA-ATO combination in non-APL NPM1-mutant AML patients.
Antibody-drug conjugates (ADCs) delivering pyrrolobenzodiazepine (PBD) dimers for cancer therapy
Published in Expert Opinion on Biological Therapy, 2021
SGN-CD33A, later to be named vadastuximab talirine, utilised the humanised anti-CD33 antibody h2HI2 engineered to contain cysteine at position 239 on the heavy chain. This allowed consistency in drug loading and low levels of aggregation compared to stochastic conjugation of talirine through endogenous interchain cysteines. SGN-CD33A was found to be highly active against CD33-positive human AML cell lines, regardless of MDR or p53 status [8]. It was superior to gemtuzumab ozogamicin (Mylotarg) in primary AML samples with activity demonstrated across the entire cytogenetic risk spectrum (unfavourable, intermediate and favourable). Vadastuximab talirine demonstrated complete and durable responses against subcutaneous AML xenograft models following a single dose as low as 100 µg/kg, and potent antileukaemic activity in disseminated models. In drug resistant models where gemtuzumab ozogamicin was inactive, doses up to ten-fold higher of SGN-CD33A were required. Specificity was demonstrated by lack of activity of the unconjugated antibody and equivalent dose of the free cytotoxic drug, or an unconjugated mixture of the two [8].
Antibodies to watch in 2018
Published in mAbs, 2018
Hélène Kaplon, Janice M. Reichert
Vadastuximab talirine (SGN-CD33A) is an ADC composed of a humanized anti-CD33 mAb with 2 engineered cysteine residues through which pyrrolobenzodiazepine dimer drug moieties are conjugated via a maleimidocaproyl valine-alanine dipeptide linker. The ADC was undergoing evaluation as a treatment of acute myeloid leukemia (AML) in the randomized, double-blind, placebo-controlled Phase 3 CASCADE study. In June 2017, Seattle Genetics, Inc. announced that it was discontinuing the CASCADE study following consultation with the Independent Data Monitoring Committee and after reviewing unblinded data that indicated a higher rate of deaths, including fatal infections in the vadastuximab talirine-containing arm versus the control arm of the study. Seattle Genetics also suspended patient enrollment and treatment in all of its other clinical trials of vadastuximab talirine.85
Advancements in the management of medically less-fit and older adults with newly diagnosed acute myeloid leukemia
Published in Expert Opinion on Pharmacotherapy, 2018
Laura C. Michaelis, Heidi D. Klepin, Roland B. Walter
There are a number of immunotherapeutic agents in development, though none have been approved by the FDA. In an effort to overcome some of the limitations seen with GO, vadastuximab talirine (SGN-CD33A) was developed as a novel CD33 antibody-drug conjugate employing a pyrrolobenzodiazepine dimer for cytotoxicity. Preclinical data showed very good activity of this agent [119], and the recent data from the phase 1 trial demonstrated single-agent anti-leukemia efficacy and acceptable safety [120]. However, a randomized, placebo-controlled, multicenter, phase 3 trial evaluating azacitidine or decitabine with SGN33A versus the azanucleoside alone (NCT02785900) was terminated early because of increased mortality in the combination arm, casting uncertainty on the future of this agent.