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Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Most younger patients achieve CR following treatment with the conventional 7+3 regimen, and the principal unresolved issue is how best to ensure continuing CR. The most common induction therapy consists of two courses of an anthracycline, usually daunorubicin at 60 mg/m2 per day or idarubicin at 12 mg/m2 for 3 days, and a continuous infusion of the cell cycle–specific drug cytarabine (cytosine arabinoside) at 100–200 mg/m2 per day for 71 days. Higher dose levels of anthracyclines and cytarabine have been tested and demonstrate increased toxicity without improvement in efficacy. For patients with FLT3ITD-positive AML, midostaurin or gilteritinib should be added to the intensive chemotherapy. Post-remission therapies often comprise two to four cycles of high-dose cytarabine with or without the addition of an anthracycline. Currently, there remains a debate with regard to using an intermediate dose level of cytarabine, 1000–1500 mg/m2, compared with 2000–3000 mg/m2.
Hyperkeratotic Reactions
Published in Gabriella Fabbrocini, Mario E. Lacouture, Antonella Tosti, Dermatologic Reactions to Cancer Therapies, 2019
Vincent Sibaud, Maria Vastarella
Finally, BCR-ABL inhibitors (imatinib and to a lesser extent nilotinib) may also worsen or promote psoriasis (Figure 5.2c) (42,43). It is potentially related to a downregulation of regulatory T cells. We have also observed severe flares of plaque psoriasis in hematologic patients treated with the newly approved idelalisib and gilteritinib, which target PI3Kδ and Flt3, respectively (Figure 5.2d).
Precision medicine in acute myeloid leukemia
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
New therapies are needed that can target and eradicate resistant subclones early in the disease course. An example is the multikinase inhibitor midostaurin, which when added to 7 + 3 induction has been found to benefit in patients with FLT3-mutated AML (Gallogly and Lazarus, 2016). Sorafenib (a tyrosine kinase inhibitor), crenolanib (a FLT3 inhibitor with activity against FLT3-D835 TKD mutation), gilteritinib (ASP-2215, a potent inhibitor of both FLT3-ITD and FLT3-TKD mutations), and a second-generation FLT3-ITD inhibitor quizaritinib (formerly known as AC220) were also used in combination with chemotherapy (De Kouchkovsky and Abdul-Hay, 2016; Grunwald and Levis, 2015). Terminal myeloid differentiation in vivo is induced by FLT3 inhibition in FLT3/ITD AML (Sexauer et al., 2012). Unfortunately, owing to the resistance, the responses to FLT3 inhibitors are not durable and last just 3–6 months. For patients harboring FLT3-ITD mutations, allogeneic hematopoietic stem cell transplantation (alloHSCT) is preferable, and autologous HSCT is used mainly for patients with favorable or intermediate-risk cytogenetics in first remission (Tamamyan et al., 2017).
Current and emerging pharmacotherapy for the treatment of childhood acute myeloid leukemia
Published in Expert Opinion on Pharmacotherapy, 2022
Branko Cuglievan, David McCall, Lindsay Robusto, M. Estela Mireles, Suzanne C. Gettys
Gilteritinib is an oral tyrosine kinase inhibitor with selective activity against FLT3 mutations and is FDA approved for use in adult patients with relapsed or refractory AML with an FLT3 mutation. A phase I/II study demonstrated potent FLT3 phosphorylation with doses >80 mg/day and overall response rate in 37% of patients with relapsed/refractory FLT3-mutated AML [46]. The FDA approval was secured with the phase III ADMIRAL trial results, where gilteritinib at 120 mg daily was compared with salvage chemotherapy in the relapsed/refractory setting. Patients who received gilteritinib had a significantly longer OS (9.3 vs 5.6 months, p < 0.001) and higher remission rates (CR 21.1% vs 10.5%) compared to those receiving salvage chemotherapy. Grade 3 or higher adverse effects were less common in the gilteritinib group [47]. Follow-up data demonstrated an improved 2-year OS rate for the gilteritinib arm (20.6% vs 14.2%) and a median CR duration of 23 months. A total of 62% of patients in the gilteritinib arm underwent HSCT and continued gilteritinib as post-HSCT maintenance therapy. The most common adverse effects noted were elevated alanine aminotransferase and aspartate aminotransferase, usually grade 1 or 2 [48].
Pharmacoeconomic considerations for acute myeloid leukemia pharmacotherapy
Published in Expert Opinion on Pharmacotherapy, 2022
Monia Marchetti, Luca Albertin, Giulia Limberti, Manuela Canicattì
Gilteritinib is a second-generation FLT3 inhibitor that has been tested in relapsed/refractory FLT3-mutated AML patients. The ADMIRAL trial reported a median OS increase from 5.6 to 9.3 months as compared with standard salvage chemotherapy (LDAC, AZA, MEC, FLAG-IDA). In patients not previously exposed to FLT3 inhibitors, gilteritinib improved OS with an HR of 0.620 (95% CI; 0.470–0.818), while for the 11–13% patients with prior use of midostaurin the treatment difference was not statistically significant (HR 0.705; 95% CI 0.346 to 1.438) [42]. NICE appraised a pharmacoeconomic model considering the cost of gilteritinib to be £14,188 per 28-day pack (minus a confidential discount to NHS) and based on the clinical results of the ADMIRAL trial. The exploratory analysis, which included OS data of randomized patients undergoing SCT, reported that the incremental cost per QALY saved by gilteritinib monotherapy increased from £54,844 – which is acceptable for an end-of-life treatment – to £95,642, and that incremental utility decreased to 0.74 QALYs [43].
Safety of FLT3 inhibitors in patients with acute myeloid leukemia
Published in Expert Review of Hematology, 2021
Claudio Cerchione, Andrés Peleteiro Raíndo, Adrián Mosquera Orgueira, Alicia Mosquera Torre, Laura Bao Pérez, Giovanni Marconi, Alessandro Isidori, Manuel Mateo Pérez Encinas, Giovanni Martinelli
Gilteritinib is generally well tolerated. In the ADMIRAL trial, the incidence of all exposure-adjusted adverse events was higher in the chemotherapy group than in the gilteritinib group, including those that were considered by the investigator to be drug-related. Considering adverse events that occurred during the first 30 days of treatment, similar results were obtained in both groups, except for elevations of the liver aminotransferase levels, which were slightly higher in the gilteritinib group. In the gilteritinib group, the most common grade ≥3 adverse events were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%), which were also the most common grade ≥3 gilteritinib-related adverse events according to the investigators. The incidence of grade ≥3 exposure-adjusted adverse events was 42.44 events per patient-year in the chemotherapy group and 19.34 events per patient-year in the gilteritinib group. QT interval prolongation related to gilteritinib occurred in 4.9% of patients, but only 1 patient (0.4%) had a maximum post-baseline increase in the mean corrected QT interval above 500 msec [56]. In other clinical studies, the most common adverse events related to Gilteritinib consisted of diarrhea (16%), anemia (33%), fatigue (15%) and elevated liver function tests (elevated AST 13%, elevated ALT 10%). The most common grade 3–4 adverse events developed were neutropenia (8.2%), anemia (24.4%), thrombopenia (12.8%), sepsis (14%), and pneumonia (12%) [55].