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Review

Safety of FLT3 inhibitors in patients with acute myeloid leukemia

ORCID Icon, , , , , , , ORCID Icon & show all
Pages 851-865 | Received 01 May 2021, Accepted 13 Aug 2021, Published online: 30 Aug 2021

References

  • Walter MJ, Payton JE, Ries RE, et al. Acquired copy number alterations in adult acute myeloid leukemia genomes. Proc Natl Acad Sci USA. 2009;106(31):12950–12955.
  • Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209–2221.
  • Bacher U, Haferlach C, Kern W, et al. Prognostic relevance of FLT3-TKD mutations in AML: the combination matters—an analysis of 3082 patients. Blood. 2008;111(5):2527–2537.
  • Daver N, Schlenk RF, Russell NH, et al. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019;33(2):299–312.
  • Sexauer A, Perl A, Yang X, et al. Terminal myeloid differentiation in vivo is induced by FLT3 inhibition in FLT3/ITD AML. Blood. 2012;120(20):4205–4214.
  • Weis TM, Marini BL, Bixby DL, et al. Clinical considerations for the use of FLT3 inhibitors in acute myeloid leukemia. Crit Rev Oncol Hematol. 2019;141:125–138.
  • Larrosa-Garcia M, Baer MR. FLT3 inhibitors in acute myeloid leukemia: current status and future directions. mol Cancer Ther. 2017;16(6):991–1001.
  • Levis M, Pham R, Smith BD, et al. In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects. Blood. 2004;104(4):1145–1150.
  • Mosquera O, Bao P, Mosquera T, et al. FLT3 inhibitors in the treatment of acute myeloid leukemia: current status and future perspectives. Minerva Med. 2020;111. doi: https://doi.org/10.23736/S0026-4806.20.06989-X.
  • Rydapt®. Drug data sheet. Eudra; [Internet]. [cited 2020, May 26]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/rydapt [ cited 2020, May 26].
  • Stone RM, Mandrekar SJ, Sanford BL, et al., Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5): 454–464.
  • Schlenk RF, Weber D, Fiedler W, et al. Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood. 2019;133(8):840–851.
  • Midostaurin BC cancer agency cancer drug manual. http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Midostaurin_monograph.pdf .
  • Galanis A, Ma H, Rajkhowa T, et al. Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants. Blood. 2014;123(1):94–100.
  • Johan A, Corrado G, Roger J, et al. European guidelines for primary antifungal prophylaxis in adult haematology patients: summary of the updated recommendations from the European conference on infections in leukaemia. J Antimicrob Chemother. 2018;73:3221–3230.
  • Stemler J, Koehler P, Maurer C, et al. Antifungal prophylaxis and novel drugs in acute myeloid leukemia: the midostaurin and posaconazole dilemma. Ann Hematol. 2020 Jul;99(7):1429–1440. Epub 2020 Jun 8. PMID: 32514626; PMCID: PMC7316674.
  • Lindsay J, Teh BW, Micklethwaite K, et al. Azole antifungals and new targeted therapies for hematological malignancy. Curr Opin Infect Dis. 2019;32(6):538–545.
  • Schlafer D. Management of Midostaurin-CYP3A4 drug-drug interactions in patients with acute myeloid leukemia. Oncology (Williston Park). 2019;33(7):629381.
  • Noxafil® (posaconazole)—prescribing information (2019). Merck & Co Inc., Whitehouse Station.
  • Rothe A, Classen A, Carney J, et al. Bridging antifungal prophylaxis with 50 mg or 100 mg micafungin in allogeneic stem cell transplantation: a retrospective analysis. Eur J Haematol. 2019;104(4):291–298.
  • Van Burik JA, Ratanatharathorn V, Stepan DE, et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis. 2004;39(10):1407–1416.
  • Park H, Youk J, Shin DY, et al. Micafungin prophylaxis for acute leukemia patients undergoing induction chemotherapy. BMC Cancer. 2019;19(1):358.
  • Park S, Kim K, Jang JH, et al. Randomized trial of micafungin versus fluconazole as prophylaxis against invasive fungal infections in hematopoietic stem cell transplant recipients. J Inf Secur. 2016;73(5):496–505.
  • Epstein DJ, Seo SK, Huang YT, et al. Micafungin versus posaconazole prophylaxis in acute leukemia or myelodysplastic syndrome: a randomized study. J Inf Secur. 2018;77(3):227–234.
  • Fisher BT, Zaoutis T, Dvorak CC, et al. Effect of caspofungin vs fluconazole prophylaxis on invasive fungal disease among children and Young adults with acute myeloid leukemia: a randomized clinical trial. Jama. 2019;322(17):1673–1681.
  • Mattiuzzi GN, Alvarado G, Giles FJ, et al. Open-label, randomized comparison of itraconazole versus caspofungin for prophylaxis in patients with hematologic malignancies. Antimicrob Agents Chemother. 2006;50(1):143–147.
  • Groll AH, Stergiopoulou T, Roilides E, et al. Micafungin: pharmacology, experimental therapeutics and clinical applications. Expert Opin Investig Drugs. 2005;14(4):489–509.
  • Rosa PDD, Ramirez-Castrillon M, Borges R, et al. Epidemiological aspects and characterization of the resistance profile of Fusarium spp. in patients with invasive fusariosis. J Med Microbiol. 2019;68(10):1489–1496.
  • Pagano L, Busca A, Candoni A, et al. Risk stratification for invasive fungal infections in patients with hematological malignancies: SEIFEM recommendations. Blood Rev. 2017;31(2):17–29.
  • Cornely OA, Alastruey-Izquierdo A, Arenz D, et al. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European confederation of medical mycology in cooperation with the mycoses study group education and research consortium. Lancet Infect Dis. 2019;19(12):e405–e421.
  • Cornely OA, Bohme A, Schmitt-Hoffmann A, et al. Safety and pharmacokinetics of isavuconazole as antifungal prophylaxis in acute myeloid leukemia patients with neutropenia: results of a phase 2, dose escalation study. Antimicrob Agents Chemother. 2015;59(4):2078–2085.
  • Bose P, McCue D, Wurster S, et al. Isavuconazole as primary anti-fungal prophylaxis in patients with acute myeloid leukemia or myelodysplastic syndrome: an open-label, prospective. Phase II Study Clin Infect Dis. 2020;doi: https://doi.org/10.1093/cid/ciaa358
  • CRESEMBA® (Isavuconazoium)—prescribing information (2019). Astellas Pharma US Inc., Northbrook.
  • Marty FM, Ostrosky-Zeichner L, Cornely OA, et al. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis. 2016;16(7):828–837.
  • Fung M, Schwartz BS, Doernberg SB, et al. Breakthrough invasive fungal infections on Isavuconazole prophylaxis and treatment: what is happening in the real-world setting? Clin Infect Dis. 2018;67(7):1142–1143.
  • Rausch CR, DiPippo AJ, Bose P, et al. Breakthrough fungal infections in patients with leukemia receiving Isavuconazole. Clin Infect Dis. 2018;67(10):1610–1613.
  • Fontana L, Perlin DS, Zhao Y, et al. Isavuconazole prophylaxis in patients with hematologic malignancies and hematopoietic cell transplant recipients. Clin Infect Dis. 2020 Feb 14;70(5):723–730. PMID: 30958538; PMCID: PMC7931837.
  • Stern A, Su Y, Lee YJ, et al. A single-Center, open-Label trial of isavuconazole prophylaxis against invasive fungal infection in patients undergoing allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2020 Jun;26(6):1195–1202. Epub 2020 Feb 20. PMID: 32088367; PMCID: PMC8210627.
  • Mattiuzzi GN, Cortes J, Alvarado G, et al. Efficacy and safety of intravenous voriconazole and intravenous itraconazole for antifungal prophylaxis in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome. Support Care Cancer. 2011;19(1):19–26.
  • A. Sierra J, Montesinos P, Thomas X. 632 phase 3b study assessing the safety and efficacy of midostaurin in younger and older patients with newly diagnosed, FLT3-Mutated Acute Myeloid Leukemia (AML) who are eligible for 7+3 or 5+2 chemotherapy. https://ash.confex.com/ash/2020/webprogram/Paper136083.html
  • Burchert A, Bug G, Finke J, et al. Sorafenib as maintenance therapy post allogeneic stem cell transplantation for FLT3-ITD positive AML: results from the randomized, double-blind, placebo-controlled multicentre sormain trial Blood. 2018;132 (Supplement 1):661. Available from: https://doi.org/10.1182/blood-2018-99-112614
  • Wilhelm S, Carter C, Lynch M, et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006;5(10):835–844.
  • Bayer HealthCare. 2018. NEXAVAR (sorafenib). U.S. food and drug administration. [Internet]. [ cited 2020 Aug 21]. Available from: www.accessdata.fda.gov/drugsatfda_docs/label/2018/021923s020lbl.pdf
  • Liu T, Ivaturi V, Sabato P, et al. Sorafenib dose recommendation in acute myeloid leukemia based on exposure-FLT3 relationship. Clin. Transl. Sci. 2018;11(4):435–443.
  • Xuan L, Wang Y, Huang F. Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. Lancet Oncol. 2020 Sep;21(9):1201–1212.
  • Blanchet B, Billemont B, Barete S, et al. Toxicity of sorafenib: clinical and molecular aspects. Expert Opin Drug Saf. 2010 Mar;9(2):275–287. PMID: 20078249.
  • Sorafenib BC Cancer Agency Cancer Drug Manual. Available from: http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Sorafenib_monograph_1Dec2014.pdf
  • Porta C, Paglino C, Imarisio I, et al. Uncovering Pandora’s vase: the growing problem of new toxicities from novel anticancer agents. The case of sorafenib and sunitinib. Clin Exp Med. 2007;7(4):127–134.
  • Yang CH, Lin WC, Chuang CK, et al. Hand-foot skin reaction in patients treated with sorafenib: a clinicopathological study of cutaneous manifestations due to multitargeted kinase inhibitor therapy. Br J Dermatol. 2008;158(3):592–596.
  • Beldner M, Jacobson M, Burges GE, et al. Localized palmar-plantar epidermal hyperplasia: a previously undefined dermatologic toxicity to sorafenib. Oncologist. 2007;12(10):1178–1182.
  • Torino F, Corsello SM, Longo R, et al. Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy. Nat Rev Clin Oncol. 2009;6(4):219–228.
  • Ravandi F, Cortes JE, Jones D, et al. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol. 2010 Apr 10;28(11):1856–1862. Epub 2010 Mar 8. PMID: 20212254; PMCID: PMC2930809.
  • Park IK, Mundy-Bosse B, Whitman SP, et al. Receptor tyrosine kinase Axl is required for resistance of leukemic cells to FLT3-targeted therapy in acute myeloid leukemia. Leukemia. 2015;29(12):2382–2389.
  • Park IK, Mishra A, Chandler J, et al. Inhibition of the receptor tyrosine kinase Axl impedes activation of the FLT3 internal tandem duplication in human acute myeloid leukemia: implications for Axl as a potential therapeutic target. Blood. 2013;121(11):2064–2073.
  • Astellas Pharma. XOSPATA (gilteritinib). U.S. Food and drug administration; 2019 [Internet].  [cited 2020 Aug 21]. Available from: www.accessdata.fda.gov/drugsatfda_docs/label/2019/211349s001lbl.pdf.
  • Perl AE, Martinelli G, Cortes JE, et al., Gilteritinib or chemotherapy for relapsed or refractory FLT3-Mutated AML. N Engl J Med. 2019;381(18): 1728–1740.
  • Jianke L, Bresnahan G, Sanga M, et al., Absorption, metabolism, and excretion of quizartinib (AC220), a FLT3 tyrosine kinase inhibitor for treatment of acute myeloid leukemia, in healthy male volunteers. Blood. 2012;120(21):4327.
  • Cortes JE, Khaled S, Martinelli G, et al., Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, openlabel, phase 3 trial. Lancet Oncol. 2019;20(7): 984–997.
  • Bazarbachi AH, Al Hamed R, Malard F, et al. Allogeneic transplant for FLT3-ITD mutated AML: a focus on FLT3 inhibitors before, during, and after transplant. Ther Adv Hematol. 2019;10:2040620719882666.
  • Cortes JE, Tallman MS, Schiller GJ, et al. Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD-mutated, relapsed or refractory AML. Blood. 2018;132(6):598–607.
  • 2014. Study of crenolanib in combination with chemotherapy in patients with relapsed or refractory acute myeloid leukemia and activating FLT3 mutations. ClinicalTrials.gov, [ cited 2020 Aug 19. [Internet]. Available from: https://clinicaltrials.gov/ct2/show/NCT02298166
  • Short NJ, Kantarjian H, Ravandi F, et al. Emerging treatment paradigms with FLT3 inhibitors in acute myeloid leukemia. Ther Adv Hematol. 2019;10:2040620719827310.
  • Stone RM, Wang ES, Goldberg AD, et al. Crenolanib versus midostaurin combined with induction and consolidation chemotherapy in newly diagnosed FLT3 mutated AML. J Clin Oncol. 2019;37(15_suppl): TPS7068.
  • Altman JK, Foran JM, Pratz KW, et al. Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Am J Hematol. 2018;93(2):213–221.
  • Pratz K, Cherry M, Altman JK, et al. Preliminary results from a phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in subjects with newly diagnosed Acute Myeloid Leukemia (AML). Blood. 2017;130:722.
  • Erba HP, Levis MJ, Sekeres MA, et al. Phase 3 (P3) study of quizartinib (Q) or placebo (P) with induction (IND) and consolidation chemotherapy (CON) and as maintenance (MN) in patients (pts) with newly diagnosed (NDx) FLT3-ITD–positive acute myeloid leukemia (AML): the QuANTUM-First study. J Clin Oncol. 2016;34: TPS7073.
  • Luger SM, Sun Z, Loghavi S, et al. Phase II randomized trial of gilteritinib vs midostaurin in newly diagnosed FLT3 mutated Acute Myeloid Leukemia (AML). Blood. 2019;134(Supplement_1):1309.
  • Naina HV, Patnaik MM, Harris S. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009;361: 2578. author reply 2578.
  • Ohanian M, Garcia-Manero G, Levis M, et al. Sorafenib combined with 5-azacytidine in older patients with untreated FLT3-ITD Mutated Acute Myeloid leukemia. Am J Hematol. 2018;93(9):1136–1141.
  • A study of ASP2215 (gilteritinib) by itself, ASP2215 combined with azacitidine or azacitidine by itself to treat adult patients who have recently been diagnosed with acute myeloid leukemia with a FLT3 gene mutation and who cannot receive standard chemotherapy. ClinicalTrials.gov; 2016 [Internet]. Available from: https://clinicaltrials.gov/ct2/show/NCT02752035 [ cited 2020 Aug 2].
  • Esteve J, Schots R, Del Castillo TB, et al. Multicenter, open-Label, 3-Arm study of gilteritinib, gilteritinib plus azacitidine, or azacitidine alone in newly diagnosed FLT3 Mutated (FLT3mut+) Acute Myeloid Leukemia (AML) patients ineligible for intensive induction chemotherapy: findings from the safety cohort. Blood. 2018;132:2736.
  • Maziarz RT, Patnaik MM, Scott BL, et al. Radius: phase A. 2 randomized trial investigating standard of care ± midostaurin after allogeneic stem cell transplant in FLT3-ITDMutated AML. Blood. 2018;132:662.
  • Metzelder SK, Schroeder T, Lu¨ Bbert M, et al. Long-term survival of sorafenib-treated FLT3-ITD–positive acute myeloid leukaemia patients relapsing after allogeneic stem-cell transplantation. Eur J Cancer. 2017;86:233–239.
  • Brunner AM, Li S, Fathi AT, et al. Haematopoietic cell transplantation with and without sorafenib maintenance for patients with FLT3-ITD acute myeloid leukaemia in first complete remission. Br J Haematol. 2016;175(3):496–504.
  • Mark J, Chen Y-B, Mehdi H, et al. FLT3 inhibitor maintenance after allogeneic transplantation: is a Placebo-Controlled, randomized trial ethical? J clin oncol. 2019 Jul 1;37(19):1604-1607. DOI: https://doi.org/10.1200/JCO.19.00321. Epub 2019 Apr 29.
  • Levis MJ, Hamadani M, Logan B, et al. A phase 3, trial of gilteritinib, as maintenance therapy after allogeneic hematopoietic stem cell transplantation in patients with FLT3-ITD+ AML. J Clin Oncol. 2018;3615_suppl. Available from: https://ascopubs.org/doi/10.1200/JCO.2018.36.15_suppl.TPS7075
  • Ruutu T, Gratwohl A, de Witte T, et al. Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice. Bone Marrow Transplant. 2014 Feb;49(2):168-73. DOI: https://doi.org/10.1038/bmt.2013.107. Epub 2013 Jul 29.
  • Novartis Pharmaceuticals. Neoral (Cyclosporine modified) Package Insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.
  • Novartis Pharmaceuticals. Rydapt (Midostaurin) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2018.
  • Mancini R, LaMontagne L, Williams T, et al. Midostaurin and cyclosporine drug interaction: a case report. J Clin Pharm Ther. 2020 Apr;45(2):384–387. Epub 2019 Nov 29. PMID: 31782821.
  • Schmid C, Labopin M, Nagler A, et al. Acute leukaemia working party of the European Group for Blood and Marrow Transplantation (EBMT). Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood. 2012;119(6):1599–1606.
  • Serve H, Krug U, Wagner R, et al. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol. 2013;31(25):3110–3118.
  • Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013;121(23):4655–4662.
  • DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018;19(2):216–228.
  • Kohl TM, Hellinger C, Ahmed F, et al. BH3 mimetic ABT-737 neutralizes resistance to FLT3 inhibitor treatment mediated by FLT3-independent expression of BCL2 in primary AML blasts. Leukemia. 2007;21(8):1763–1772.
  • Isidori A, Cerchione C, Daver N, et al. Immunotherapy in Acute Myeloid Leukemia: where we stand. Front Oncol. 2021 May 10;11:656218. eCollection 2021. PMID: 34041025.
  • Cerchione C, Romano A, Daver N, et al. IDH1/IDH2 inhibition in Acute Myeloid Leukemia. Front Oncol. 2021 Mar 29;11:639387. eCollection 2021. PMID: 33898313.
  • Mosquera Orgueira A, Peleteiro Raíndo A, Cid López M, et al. Personalized survival prediction of patients with Acute Myeloblastic Leukemia using gene expression profiling. Front Oncol. 2021 Mar 29;11:657191. eCollection 2021. PMID: 33854980.
  • Martelli MP, Martino G, Cardinali V, et al. Enasidenib and ivosidenib in AML. Minerva Med. 2020 Oct;111(5):411–426. Epub 2020 Sep 21. PMID: 32955829.
  • Gottardi M, Sperotto A, Ghelli Luserna Di Rorà A, et al. Gemtuzumab ozogamicin in acute myeloid leukemia: past, present and future. Minerva Med. 2020 Oct;111(5):395–410. Epub 2020 Sep 21. PMID: 32955828.
  • Cafaro A, Giannini MB, Silimbani P, et al. CPX-351 daunorubicin-cytarabine liposome: a novel formulation to treat patients with newly diagnosed secondary acute myeloid leukemia. Minerva Med. 2020 Oct;111(5):455–466. Epub 2020 Sep 21. PMID: 32955826.
  • Palmieri R, Buccisano F, Maurillo L, et al. Current strategies for detection and approach to measurable residual disease in acute myeloid leukemia. Minerva Med. 2020 Oct;111(5):386–394. Epub 2020 Sep 21. PMID: 32955825.
  • Takami A. Hematopoietic stem cell transplantation for acute myeloid leukemia. Int J Hematol. 2018;107(5):513–518.
  • Marconi G, Giannini MB, Bagnato G, et al. The safety profile of FLT3 inhibitors in the treatment of newly diagnosed or relapsed/refractory acute myeloid leukemia. Expert Opin Drug Saf. 2021;20(7):791–799. epub ahead of print.