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29 april 2017: Bron: FDA - Food and Drug Administration en J Cancer Res Clin Oncol. 2017 Feb;143(2):337-345.

De FDA geeft toestemming voor gebruik van Midostaurin (Merknaam Rydapt) naast chemo bij volwassen patiënten met een nieuwe diagnose van AML - Acute Myeloide Leukemie welke een FLT3 mutatie hebben . Al eerder gaven zij toestemming voor gebruik van midostaurin bij gevorderde AML - Actue Myeloide Leukemie.

De FDA geeft de toestemming op basis van verschillende fase III studies die allemaal, ook bij AML - Acute Myeloide Leukemie met geen FLT3 mutatie, een verbeterde levensverlenging gaven te zien. Echter bij die patiënten met een FLT3 mutatie waren de resultaten van midostaurin statistisch significant. De FLT3 mutatie wordt gemeten via de zogeheten LeukoStrat CDx FLT3 Mutation Assay (Invivoscribe Technologies).

De FLT3 mutatie wordt gevonden bij 30% tot 35% van de patiënten met AML en verhoogde FLT3 expressie wordt geassocieerd met een slechtere prognose van de levensduur. Wanneer de patienten Midostaurin (Ryadt) naast hun chemo krijgen stijgt de mediane overall overleving: 8,7 maanden versus 3 maanden. Maar bij deze patiënten kwamen ook langdurige totale remissies voor nadat zij Midostaurin gebruikten.

Midostaurin Molecuul

In dit studierapport: Midostaurin: an emerging treatment for acute myeloid leukemia patients wordt een review gegeven van de meeste studies die zijn gedaan met midostaurin de afgelopen tien jaar. Onderaan staat abstract:. Hier een overzicht van een aantal studies. (Tekst gaat onder grafiek verder):

Table 1

Published clinical trials of midostaurin: single-agent trials and combination-agent trials

Reference	N	Study population	FLT3	Phase	Treatment (PO)	Key results	Comments
Single-agent trials
16	32	Refractory or unresponsive solid tumors	Not reported	I	Dose escalation (midostaurin 12.5 mg PO daily to 100 mg PO TID)	First to report C_max, t_1/2 in study subjects. Most common AEs: nausea, vomiting, fatigue, diarrhea. 225–300 mg/d considered too toxic for future study	First in human dose-escalation study Correlatives (PKC inhibition) reported separately
17	30	Advanced MDS Relapsed/refractory AML Newly diagnosed AML ineligible for induction chemotherapy	mut (90% ITD)	IIB 2-stage	Midostaurin 75 mg PO TID	Most common AEs: nausea, vomiting 3 fatal pulmonary events 70% had reduction of >50% in peripheral blast count; 30% had >50% reduction in BM blast count 2 went onto BMT after initial response	First trial in AML or MDS Correlative: pFLT3 was decreased in peripheral blood monocytes and bone marrow aspirate in the subset of patients tested (n=5); all responded
23	95	Relapsed/refractory AML Newly diagnosed AML ineligible for induction chemotherapy MDS (RAEB ± transformation or CML)	WT (63%) mut (37%) (76% ITD)	IIB	Midostaurin 50 PO BID or 100 mg PO BID	Best response: PR in 1% HI: 46% FLT3 mut, 35% FLT3-WT BR: 71% FLT3 mut, 42% FLT3-WT Higher BR in previously untreated patients ND in median onset of BR (29 days) or TTF between FLT3-WT and mut patients BR correlated to drug (and metabolite) concentrations in plasma	First trial to compare responses in WT versus mut FLT3 Trough concentrations of midostaurin (and metabolites) reported
Combination trials
20	69	Newly diagnosed AML, age 18–60 years	WT (72%) mut (28%)	IB	6 dose schedules of 50–100 mg BID midostaurin with standard daunorubicin and cytarabine induction (3+7)	Most common AEs: hematologic 100 mg BID: CR in 45% (35% WT, 83% mut); 79% discontinuation rate 50 mg BID: CR in 80% (74% WT, 92% mut) ND in OS at 1 and 2 years (WT vs mut) Superior tolerance with sequential vs concomitant administration Possible pharmacokinetic interaction with daunorubicin	First combination trial with 7+3 Defined dosing schedule for Phase III trial NCT00651261, in progress
13	16	Newly diagnosed AML, age ≥18 years, not eligible for std induction Relapsed/refractory AML, age ≥18 years	WT (87%) mut (13%)	I	Decitabine days 1–5 Midostaurin days 8–21 (25–50 mg PO BID) or days 1–28 (50 mg PO BID)	Most common AEs: hematologic 2 fatal complications of viral PNA 3 DLTs (cardiac or pulmonary) CR + CRi: 25% (duration 28–331 days) No detectable pharmacokinetic interaction with decitabine	First combination trial with decitabine Preclinical correlatives suggested synergy with decitabine (in apoptosis, FLT3 phosphorylation and downstream signaling)
18	54	Untreated and previously treated AML or high-risk MDS	WT (26%) mut (74%) (68% ITD, 6% ITD + D835Y)	I/II	Azacitidine (IV or SC) days 1–7 Midostaurin days 8–21 (25–50 mg BID) up to 12 cycles	Grade 3–4 hematological AEs in 100%; Grade 3–4 nonhematological toxicity in 70% BR: 84% (PB) 53% (BM) ORR 26% (33% in FLT3-ITD pts w/o prior exposure to FLT3 inhibitors), CR 2%, CRi 11%, MLFS 11%, PR 1% (74% were primary refractory) FLT3-ITD mut was not a/w ORR Median RD: 20 weeks No detectable pharmacokinetic interactions with azacitidine	First combination trial with azacytidine Correlative: pFLT3
24	17	Untreated AML, age ≥70 years Relapsed AML, any age	WT (100%) mut (0%)	I	Aza (75 mg/m²) days 1–7 Midostaurin days 8–21 (25, 50, or 75 mg PO BID)	Most common AEs: hematologic 3 G3 GI toxicities; 1 required hospitalization CR in 3 patients (12%; duration 7, 12, 12 m) RR 18%	Only study to report patient compliance (high)

Abbreviations: AE, adverse event; AML, acute myeloid leukemia; BM, bone marrow; BMT, bone marrow transplant; BR, blast response; CR, complete remission; CRi, CR with incomplete bone marrow recovery; DLT, dose limiting toxicity; FLT3, fms-like tyrosine kinase; G, grade; HI, hematologic improvement; ITD, internal tandem duplication; m, months; MDS, myelodysplastic syndrome; MLFS, morphologic leukemia free status; ORR, overall response rate; PB, peripheral blood; PNA, pneumonia; PR, partial response; TTF, time to treatment failure; WT, wild type; mut, mutation; Aza, azacitidine; PO, by mouth; PKC, protein kinase C; RAEB, refractory anemia with excess blasts; CML, chronic myeloid leukemia; ND, no difference; IV, intravenous; SC, subcutaneous; RD, response duration; a/w; associated with; GI, gastrointestinal; OS, overall survival; BID, twice daily; TID, three times daily; RR, response rate; std, standard; w/o, without.

Zie deze studie opzet hoe het studieprotocol eruit zag / ziet: Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

Hier een grafiek van de overall overleving. Tekst gaat verder onder de grafieken

Fig 3

An external file that holds a picture, illustration, etc.
Object name is nihms584703f3.jpg

a. Overall survival probability in patients with FLT3–wild-type and FLT3-mutant AML treated on dose schedule III. Overall survival was assessed without censoring for alternative therapies such as stem cell transplant.

b. Disease-free survival probability in patients with FLT3–wild-type and FLT3-mutant AML treated on dose schedule III.

Open boxes represent values from patients on the concomitant arm (day 1-7 and day 15-22 dosing); closed circles represent values from patients on the sequential arm (day 8-22 dosing).

Hier een schema van de dosering zoals die is gebruikt bij de meeste studies:

Ook in deze studie al uit 2012: Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia blijkt midostautin een veel betere mediane overleving te geven bij jongere patienten met AML met veel complete remissies:

De complete remissies voor de midostaurin 50-mg 2x per dag dosering werd bereikt bij 80% (FLT3–wild-type: 20 van de 27 patiënten [74%], en met een FLT3 mutatie bij 12 van de 13 patiënten [92%]). Overall overleving (OS) voor patienten met een FLT3-mutant AML waren daarin min of meer gelijk in verschillen na 1 en 2 jaar (0.85 en 0.62, respectievelijk) aan de FLT3–wild-type deelnemers (0.78 en 0.52, respectivelijk). Midostaurin in combinatie met standaard chemotherapie toont een hoge complete remissie response en overall overlevingscijfers bij nieuw gediagnosteerde jong volwassenen met AML - Acute Myeloide Leukemie en werd algemeen genomen goed getolereerd op een dosis van 50 mg2x per dag gedurende 14 dagen.

In deze studie: Outcome of FLT3-ITD-positive acute myeloid leukemia: impact of allogeneic stem cell transplantation and tyrosine kinase inhibitor treatment. werd onderzocht wat het effect is van een FLT3 mutatie wanneer patiënten met AML een allogene beenmergtransplantatie krijgen:

CONCLUSIE:

This "real-life" data reflect the continuing challenge of FLT3-ITD-positive AML and confirm the poor outcome even after allogeneic SCT. Furthermore, efficacy of TKI treatment of relapsed or refractory FLT3-ITD AML is still limited and requires substantial improvement, e.g., by the introduction of second-generation inhibitors targeting constitutively active FLT3.

Samenvattend: Een FLT3 mutatie is een voorspeller van een slechte prognose, zelfs bij een allogene stamceltransplantatie. Medicijnen die effectief werkzaam zijn op deze FLT3 mutatie zijn dan ook noodzakelijk voor patiënten met AML - Acute Myeloide Leukemie.

Abstract van de reviewstudie: Midostaurin: an emerging treatment for acute myeloid leukemia patients welke gratis is in te zien staat hieronder met referentieliijst onderaan artikel:

Administration of midostaurin to relapsed/refractory MDS and AML patients confers a robust anti-blast response sufficient to bridge a minority of patients to transplant. In combination with histone deacetylase inhibitors, responses appear comparable to historic controls, while the addition of midostaurin to standard induction chemotherapy may prolong survival in FLT3-ITD mutant patients.

. 2016; 7: 73–83.

Published online 2016 Apr 19. doi: 10.2147/JBM.S100283

PMCID: PMC4848023

Midostaurin: an emerging treatment for acute myeloid leukemia patients

Molly Megan Gallogly and Hillard M Lazarus

Author information ► Copyright and License information ►

This article has been cited by other articles in PMC.

Abstract

Acute myeloid leukemia (AML) is a hematologic malignancy that carries a poor prognosis and has garnered few treatment advances in the last few decades. Mutation of the internal tandem duplication (ITD) region of fms-like tyrosine kinase (FLT3) is considered high risk for decreased response and overall survival. Midostaurin is a Type III receptor tyrosine kinase inhibitor found to inhibit FLT3 and other receptor tyrosine kinases, including platelet-derived growth factor receptors, cyclin-dependent kinase 1, src, c-kit, and vascular endothelial growth factor receptor. In preclinical studies, midostaurin exhibited broad-spectrum antitumor activity toward a wide range of tumor xenografts, as well as an FLT3-ITD-driven mouse model of myelodysplastic syndrome (MDS). Midostaurin is orally administered and generally well tolerated as a single agent; hematologic toxicity increases substantially when administered in combination with standard induction chemotherapy. Clinical trials primarily have focused on relapsed/refractory AML and MDS and included single- and combination-agent studies. Administration of midostaurin to relapsed/refractory MDS and AML patients confers a robust anti-blast response sufficient to bridge a minority of patients to transplant. In combination with histone deacetylase inhibitors, responses appear comparable to historic controls, while the addition of midostaurin to standard induction chemotherapy may prolong survival in FLT3-ITD mutant patients. The response of some wild-type (WT)-FLT3 patients to midostaurin therapy is consistent with midostaurin’s ability to inhibit WT-FLT3 in vitro, and also may reflect overexpression of WT-FLT3 in those patients and/or off-target effects such as inhibition of kinases other than FLT3. Midostaurin represents a well-tolerated, easily administered oral agent with the potential to bridge mutant and WT-FLT3 AML patients to transplant and possibly deepen response to induction chemotherapy. Ongoing studies are investigating midostaurin’s role in pretransplant induction and posttransplant consolidation therapy

Conclusion

Midostaurin’s inhibition of WT and mutant FLT3, ease of administration, and general good tolerance make it an attractive agent in the limited armamentarium of treatments for FLT3-mutant (and WT) AML. The preclinical and clinical studies published to date provide a starting point for the determination of midostaurin’s potential clinical utility in AML treatment. As a single agent, midostaurin has the potential to induce responses in relapsed/refractory AML or MDS that carry a minority of patients to a potentially curative HCT. When administered in combination with induction chemotherapy, midostaurin has the potential to deepen and/or prolong response. Whether midostaurin improves relapse-free survival after transplant remains an open question, which is under active investigation.

On the basis of the observations discussed earlier, we recommend that midostaurin be regarded as a single agent in relapsed/refractory AML or MDS patients who are HCT candidates as a potential bridge to curative therapy. This recommendation is independent of FLT3 mutation status given the documented response of FLT3-WT patients (though sometimes inferior to FLT3-mutated patients) to treatment. We also recommend enrollment in clinical trials of midostaurin for induction or consolidation therapy. Hopefully, the answer to important clinical questions such as how deeply midostaurin improves response to induction chemotherapy, if its use can extend duration of response after HCT, and how it compares to other emerging FLT3 inhibitors in efficacy and safety will be forthcoming.

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Footnotes

Disclosure

The authors report no conflicts of interest in this work.

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References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29. [PubMed]

2. Sanz M, Burnett A, Lo-Coco F, Lowenberg B. FLT3 inhibition as a targeted therapy for acute myeloid leukemia. Curr Opin Oncol. 2009;21(6):594–600. [PubMed]

3. Weisberg E, Boulton C, Kelly LM, et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell. 2002;1(5):433–443. [PubMed]

4. Whitman SP, Archer KJ, Feng L, et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res. 2001;61(19):7233–7239. [PubMed]

5. Frohling S, Schlenk RF, Breitruck J, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood. 2002;100(13):4372–4380. [PubMed]

6. Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18):1909–1918. [PubMed]

7. Kayser S, Schlenk RF, Londono MC, et al. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood. 2009;114(12):2386–2392. [PubMed]

8. Rockova V, Abbas S, Wouters BJ, et al. Risk stratification of intermediate-risk acute myeloid leukemia: integrative analysis of a multitude of gene mutation and gene expression markers. Blood. 2011;118(4):1069–1076. [PubMed]

9. Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079–1089. [PMC free article] [PubMed]

10. Fabbro D, Buchdunger E, Wood J, et al. Inhibitors of protein kinases: CGP 41251, a protein kinase inhibitor with potential as an anticancer agent. Pharmacol Ther. 1999;82(2–3):293–301. [PubMed]

11. Fabbro D, Ruetz S, Bodis S, et al. PKC412 – a protein kinase inhibitor with a broad therapeutic potential. Anticancer Drug Des. 2000;15(1):17–28. [PubMed]

12. Pratz KW, Sato T, Murphy KM, Stine A, Rajkhowa T, Levis M. FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML. Blood. 2010;115(7):1425–1432. [PMC free article] [PubMed]

13. Williams CB, Kambhampati S, Fiskus W, et al. Preclinical and phase I results of decitabine in combination with midostaurin (PKC412) for newly diagnosed elderly or relapsed/refractory adult patients with acute myeloid leukemia. Pharmacotherapy. 2013;33(12):1341–1352. [PubMed]

14. McDonald AC, Popper D, King D, Champain K, Graf P, Man A. Phase I and pharmacokinetic study of CGP 41521, an inhibitor of protein kinase (abstract) Proc Am Soc Clin Oncol. 1997;15(212a)

15. Wang Y, Yin OQ, Graf P, Kisicki JC, Schran H. Dose- and time-dependent pharmacokinetics of midostaurin in patients with diabetes mellitus. J Clin Pharmacol. 2008;48(6):763–775. [PubMed]

16. Propper DJ, McDonald AC, Man A, et al. Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C. J Clin Oncol. 2001;19(5):1485–1492. [PubMed]

17. Stone RM, DeAngelo DJ, Klimek V, et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005;105(1):54–60. [PubMed]

18. Strati P, Kantarjian H, Ravandi F, et al. Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome. Am J Hematol. 2015;90(4):276–281. [PMC free article] [PubMed]

19. Yin OQ, Wang Y, Schran H. A mechanism-based population pharmacokinetic model for characterizing time-dependent pharmacokinetics of midostaurin and its metabolites in human subjects. Clin Pharmacokinet. 2008;47(12):807–816. [PubMed]

20. Stone RM, Fischer T, Paquette R, et al. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia. 2012;26(9):2061–2068. [PMC free article] [PubMed]

21. Zarrinkar PP, Gunawardane RN, Cramer MD, et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML) Blood. 2009;114(14):2984–2992. [PMC free article] [PubMed]

22. Dutreix C, Munarini F, Lorenzo S, Roesel J, Wang Y. Investigation into CYP3A4-mediated drug-drug interactions on midostaurin in healthy volunteers. Cancer Chemother Pharmacol. 2013;72(6):1223–1234. [PMC free article] [PubMed]

23. Fischer T, Stone RM, Deangelo DJ, et al. Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol. 2010;28(28):4339–4345. [PMC free article] [PubMed]

24. Cooper BW, Kindwall-Keller TL, Craig MD, et al. A phase I study of midostaurin and azacitidine in relapsed and elderly AML patients. Clin Lymphoma Myeloma Leuk. 2015;15(7):428–432. e422. [PMC free article] [PubMed]

25. Stone RM MS, Sanford BL, Geyer S, et al. The multi-kinase inhibitor midostaurin (M) prolongs survival compared with placebo (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose C consolidation (consol), and as maintenance (maint) therapy in newly diagnosed acute myeloid leukemia (AML) patients (pts) age 18–60 with FLT3 mutations (muts): An international prospective randomized (rand) P-controlled double-blind trial (CALGB 10603/RATIFY ) (abstract); Paper presented at: American Society of Hematology (ASH) 57th Annual Meeting; December 3–6, 2015; Orlando, FL, USA.

26. Corces-Zimmerman MR, Majeti R. Pre-leukemic evolution of hematopoietic stem cells: the importance of early mutations in leukemogenesis. Leukemia. 2014;28(12):2276–2282. [PMC free article] [PubMed]

27. Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136–1152. [PubMed]

28. Stolzel F, Steudel C, Oelschlagel U, et al. Mechanisms of resistance against PKC412 in resistant FLT3-ITD positive human acute myeloid leukemia cells. Ann Hematol. 2010;89(7):653–662. [PubMed]

29. Heidel F, Solem FK, Breitenbuecher F, et al. Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain. Blood. 2006;107(1):293–300. [PubMed]

30. Giri S, Hamdeh S, Bhatt VR, Schwarz JK. Sorafenib in relapsed AML with FMS-like receptor tyrosine kinase-3 internal tandem duplication mutation. J Natl Compr Canc Netw. 2015;13(5):508–514. [PubMed]

31. 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. [PubMed]

32. Leung AY, Man CH, Kwong YL. FLT3 inhibition: a moving and evolving target in acute myeloid leukaemia. Leukemia. 2013;27(2):260–268. [PubMed]

33. Sudhindra A, Smith CC. FLT3 inhibitors in AML: are we there yet? Curr Hematol Malig Rep. 2014;9(2):174–185. [PubMed]

34. Grunwald MR, Levis MJ. FLT3 tyrosine kinase inhibition as a paradigm for targeted drug development in acute myeloid leukemia. Semin Hematol. 2015;52(3):193–199. [PubMed]

35. Kiyoi H. Flt3 inhibitors: recent advances and problems for clinical application. Nagoya J Med Sci. 2015;77(1–2):7–17. [PMC free article] [PubMed]

36. Cortes JE, Kantarjian H, Foran JM, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013;31(29):3681–3687. [PMC free article] [PubMed]

37. Levis MJ PA, Altman JK, Cortes JE, et al. Results of a first-in-human, phase I/II trial of ASP2215, a selective, potent inhibitor of FLT3/Axl in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) (Abstr 7003) J Clin Oncol. 2015;33 abstr 7003.

38. Zimmerman EI, Turner DC, Buaboonnam J, et al. Crenolanib is active against models of drug-resistant FLT3-ITD-positive acute myeloid leukemia. Blood. 2013;122(22):3607–3615. [PMC free article] [PubMed]

39. Thom C. Preliminary data on ASP2215: tolerability and efficacy in acute myeloid leukemia patients. Future Oncol. 2015;11(18):2499–2501. [PubMed]

40. Levis MJ PA, Dombret H, Dohner H, et al. Final results of a phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory myeloid leukemia after second-line chemotherapy or hematopoietic stem cell transplantation. Blood. 2012;120:673.

Articles from Journal of Blood Medicine are provided here courtesy of Dove Press

Leukemie, AML, Acute Myeloide Leukemie, beenmergtransplantatie, chemo, NPM1-mutatie, karyotype, overall overleving, ziektevrije tijd, midostaurin, Rydapt, FLT3 mutatie