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Midostaurin for the management of FLT3-mutated acute myeloid leukemia and advanced systemic mastocytosis

Midostaurin for the management of FLT3-mutated acute myeloid leukemia and advanced systemic... Abstract Purpose This article reviews the pharmacology, efficacy, safety, cost, and future directions of midostaurin for the treatment of acute myeloid leukemia (AML), aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm, and mast cell leukemia, collectively known as advanced systemic mastocytosis (SM). Summary Midostaurin was approved by the U.S. Food and Drug Administration for the treatment of FMS-like tyrosine kinase-3 (FLT3)- mutated AML. FLT3 is a tyrosine kinase which plays a key role in proliferation of early hematopoietic progenitor cells. In addition to having activity against FLT3, midostaurin inhibits several other tyrosine kinases which led to its approval for the treatment of advanced SM. Conclusion Midostaurin offers a novel strategy to treat both FLT3-mutated AML and advanced SM. With a comparable adverse effect profile to other agents and substantial antiproliferative activity, midostaurin offers a therapeutic option for patients who have historically been difficult to treat. antineoplastics, clinical pharmacology, leukemia, mastocytosis, oncology, pharmacokinetics KEY POINTS Midostaurin is the first agent approved for the treatment of FLT3-mutated acute myeloid leukemia (AML), and is the first new drug approved for AML since 2000. Midostaurin has been shown to be efficacious in both FLT3-ITD and FLT3-TKD mutated AML. Midostaurin inhibits several other tyrosine kinases in addition to FLT3, leading to its approval for the treatment of advanced systemic mastocytosis. Acute myeloid leukemia (AML) is the most common acute leukemia among adults, with an estimated 19,520 new cases in 2018, and accounts for the greatest number of deaths from leukemia in the United States.1 For nearly 40 years, the standard induction treatment for patients < 60 years of age has been cytarabine, given as a continuous infusion over 7 days, plus either daunorubicin or idarubicin administered daily for 3 days.2 Despite advancements in molecular profiling, AML remains difficult to treat, with an average 5-year survival rate of 27.4%.1 Cytogenetic and mutational data have allowed researchers to better predict prognostic factors and provide targetable treatment options with the potential to improve survival.3 One of the most well studied molecular markers in AML is the FMS-like tyrosine kinase-3 (FLT3). This tyrosine kinase plays a key role in proliferation of early hematopoietic progenitor cells.4 Activating mutations of the FLT3 gene on chromosome 13q12 are generally divided into 2 subgroups: internal tandem duplications (ITD) and a point mutation of the tyrosine kinase domain (TKD).5FLT3-ITD mutations are more common (found in approximately 23% of AML cases) and are correlated with shorter remission durations, leading to a reduction in overall survival (OS) when compared with FLT3 wild type.6-10 The prognostic implications of FLT3-TKD mutations (found in approximately 7% of AML cases) are less clear, with some reports suggesting that FLT3-TKD mutations have no impact on survival.8,11,12 Ultimately, the poor outcomes associated with FLT3-mutated AML led to the development of midostaurin (Rydapt, Novartis Pharmaceuticals Corporation, East Hanover, NJ), the first agent approved for the treatment of FLT3-mutated AML, and the first new drug approved for AML since 2000.13 Midostaurin is an oral small molecule, first-generation FLT3 inhibitor. In addition to inhibiting FLT3, midostaurin also has activity against KIT proto-oncogene receptor tyrosine kinase (KIT) (wild-type and D816V mutant), platelet-derived growth factor (PDGFR) α/β, vascular endothelial growth factor 2 (VEGFR2), and members of the serine/threonine kinase protein kinase C family. Because of its activity against these receptors, labeling for midostaurin was approved by the U.S. Food and Drug Administration (FDA) with indications for the treatment of aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL), collectively known as advanced systemic mastocytosis (SM).14 More than 80% of patients with advanced SM have a KIT D816V mutation, making midostaurin an effective medication for this indication.15 Advanced SM is a myeloid neoplasm caused by the accumulation of mast cells in organs such as the bone marrow, skeletal system, liver, spleen, and gastrointestinal tract. Symptoms of this disease are related to the organs affected by mast cell accumulation; it is common for these patients to develop cytopenia, osteolysis leading to fractures, hepatosplenomegaly, and weight loss, collectively referred to as C-findings.16 The prognosis for patients with advanced SM is generally quite poor, with expected survival time ranging from 3.5 years in patients diagnosed with ASM to a mere 6 months in patients with MCL.17,18 The recommended dosing of midostaurin differs based on indication for use. For newly diagnosed FLT3-mutated AML, the recommended dose of midostaurin is 50 mg orally taken twice daily with food on days 8–21 of induction chemotherapy with cytarabine and daunorubicin and again on days 8–21 of each consolidation cycle with high-dose cytarabine. The recommended dose of midostaurin for ASM, SM-AHN, or MCL is 100 mg orally taken twice daily with food until disease progression or unacceptable toxicity.14 In this article, we describe the pharmacology, efficacy, safety, cost, and future directions of midostaurin for the treatment of AML and advanced SM. Pharmacokinetics and pharmacodynamics Midostaurin is rapidly absorbed and reaches peak plasma concentrations within 1 to 3 hours post dose and is thought to have very high oral absorption (> 90%) based on the low levels of unchanged midostaurin found in the urine and feces (< 5%).19 Compared with a fasting state, the midostaurin area under the curve (AUC) is increased by 1.2-fold when given with a standard meal and 1.6-fold when given with a high-fat meal; because of these findings, it is recommended midostaurin be administered with food.14 Midostaurin appears to have a large volume of distribution (95.2 L), indicating high tissue distribution.14 Midostaurin is metabolized primarily through cytochrome P450 (CYP) isoenzyme 3A4 into two active metabolites, CGP62221 (via O-demethylation) and CGP52421 (via 7-hydroxylation).19 A recent study of healthy volunteers investigated the effects of midostaurin when given with ketoconazole and rifampin, potent CYP3A4 inhibitors and inducers, respectively. The influence of ketoconazole on midostaurin was significant, causing a 1.8-fold increase in the maximum concentration (C max) and a 10-fold increase in AUC due to decreased clearance of midostaurin. This was correlated with a higher frequency of nausea, dry skin, abdominal distension, cough, and sleep disorders when compared with placebo.20 As anticipated, CYP3A4 induction with rifampin had an opposing impact on midostaurin exposure; when given in combination with rifampin, the clearance of midostaurin increased 16.9-fold compared with placebo. Interestingly, both metabolites exhibited a similar pattern, indicating midostaurin and its metabolites are primarily cleared from the body via CYP3A4 metabolism. Efficacy data were not assessed. Given the extent of interaction with potent CYP3A4 inducers, concomitant use of midostaurin with strong or moderate inducers of CYP3A4 should be avoided.20 Midostaurin exhibits linear kinetics in the first 3 to 6 days after administration and shifts to time-dependent kinetics thereafter. This kinetic profile causes the plasma concentrations of midostaurin to decrease substantially between days 6 and 14 with steady state being reached after approximately 28 days. CGP62221 exhibits a similar pharmacokinetic profile to the parent compound, while CGP52421 plasma concentrations continue to rise following 1 month of treatment.14,20 As previously mentioned, the coadministration of midostaurin with strong CYP3A4 inhibitors may lead to increased midostaurin concentrations and consequently increased toxicities; these effects are thought to be more pronounced during the first week of therapy due to the initial phase of linear kinetics. The terminal half-life of midostaurin is nearly 21 hours, similar to CGP62221 (32 hours), but much shorter than that of CGP52421 (482 hours). Midostaurin and its metabolites are greater than 99.8% protein bound to α-1-acid glycoprotein, which may contribute to its long half-life.14 Factors such as age, sex, and mild or moderate hepatic and renal impairment have not been shown to have a clinically meaningful impact on the pharmacokinetics of midostaurin. Unfortunately, data are lacking in patients with severe hepatic impairment (total bilirubin level > 3 times the upper limit of normal and any aspartate aminotransferase [AST] above the upper limit of normal) or severe renal impairment (creatinine clearance [CLCr] of 15 to 30 mL/minute); thus, use in this patient population is not recommended.14 Efficacy AML. Historically, patients with FLT3-mutated AML had the option of being treated off-label with regimens such as decitabine and sorafenib;21 azacitidine and sorafenib;22 or idarubicin, cytarabine, and sorafenib.23 Sorafenib, like midostaurin, is a multiple kinase inhibitor with activity against FLT3 mutations. Although some patients have achieved clinical remission with sorafenib, responses are often short-lived, which prompted the investigation of midostaurin for this indication.24 A Phase IB trial (NCT0093600) was among the first to investigate the use of midostaurin for AML. Newly diagnosed patients with mutated and wild-type FLT3 AML were assigned to receive midostaurin in combination with daunorubicin and cytarabine induction therapy followed by high-dose cytarabine consolidation therapy. Patients receiving midostaurin 50 mg twice daily demonstrated high complete response (CR) rates of 80%, (74% in FLT3-wild type and 92% in FLT3-mutant AML). Of note, this study was initially designed using midostaurin 100 mg twice daily, but due to high rates of grade 3 and 4 nausea and vomiting, the dosing schedule was modified to 50 mg twice daily.25 The results from this early study provided the clinical groundwork for the CALGB 10603 (RATIFY) trial.26 The landmark RATIFY trial that led to midostaurin’s approval for AML, included 717 patients between 18 and 59 years of age with newly diagnosed FLT3-mutated AML. Once confirmation of the FLT3 mutation was obtained, patients were randomized to receive standard chemotherapy (cytarabine 200 mg/m2 given as a continuous infusion for 7 days, plus daunorubicin 60 mg/m2 administered on days 1 to 3) in combination with either midostaurin 50 mg twice daily on days 8 to 21 or placebo for up to 2 cycles of induction. Patients who achieved CR after induction therapy received four 28-day cycles of consolidation therapy with high-dose cytarabine 3000 mg/m2 every 12 hours on days 1, 3, and 5 and either placebo or midostaurin 50 mg twice daily on days 8 to 21. Those who maintained remission after consolidation therapy entered a maintenance phase where they received placebo or midostaurin 50 mg twice daily for 12 months.26 Patients were stratified according to the subtype of FLT3 mutation: TKD or ITD with either a high ratio (> 0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles. FLT3 subtype was ITD (high) in 29.8% of patients, ITD (low) 47.6% of patients, and TKD in 22.6% of patients. After the minimum follow-up duration of 3.5 years following randomization, OS was significantly longer in the midostaurin group compared with placebo (hazard ratio [HR] 0.78: OS, 74.7 months vs. 25.6 months; p = 0.009). The 4-year median OS rate was 51.4% in the midostaurin group compared with 44.3% in the placebo group. Median disease-free survival (DFS) was also improved in the midostaurin group (26.7 months vs. 15.5 months; p = 0.01). A total of 57% of patients underwent stem cell transplantation (SCT) at some point during their disease course, with 28.1% undergoing SCT during first complete remission (CR1) in the midostaurin group and 22.7% in the placebo group (p = 0.10). First complete remission was defined as the presence of less than 5% blasts in the marrow or extramedullary leukemia, an absolute neutrophil count of more than 1000 per microliter, a platelet count of more than 100,000 per microliter, and the absence of blasts in the peripheral blood. Additionally, the complete remission had to have occurred by day 60. Ultimately, results of the trial demonstrated patients receiving midostaurin for newly diagnosed FLT3-mutated AML had better median OS, event free survival, and DFS when compared with placebo.26 The results of the RATIFY trial revealed several important findings. First, no significant difference was found upon analysis of subgroups according to their FLT3 subtype. Given the prognostic implications of FLT-ITD and FLT-TKD mutations, it is theorized that patients with FLT-ITD high disease would benefit most from treatment with midostaurin, but in fact patients with FLT3-TKD mutations had the lowest OS hazard ratio (HR = 0.65).26 This finding, combined with the results from the Phase IB trial suggests that at least some component of midostaurin’s efficacy comes from its multitargeted mechanism of action. Another important finding from the RATIFY trial is that the survival curves between midostaurin and placebo separated quickly (Figure 1), suggesting benefit from midostaurin occurs early in the treatment course. This is consistent with midostaurin’s pharmacokinetic profile in which plasma concentrations are the highest during the first month of treatment.14,20 Figure 1. View largeDownload slide Kaplan–Meier curves for median overall survival in the midostaurin group and the placebo group in the RATIFY trial. Tick marks indicate censoring of data. From New Engl J Med, Stone RM, Mandrekar SJ, Sanford BL et al., Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation, 377, 454-64. Copyright © 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Figure 1. View largeDownload slide Kaplan–Meier curves for median overall survival in the midostaurin group and the placebo group in the RATIFY trial. Tick marks indicate censoring of data. From New Engl J Med, Stone RM, Mandrekar SJ, Sanford BL et al., Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation, 377, 454-64. Copyright © 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. A post-hoc analysis of the RATIFY trial was recently conducted by Larson and colleagues27 to investigate a subset of patients achieving CR that were subsequently started on maintenance therapy. This analysis included 105 patients receiving maintenance therapy with midostaurin and 69 patients receiving placebo. Surprisingly, DFS was not found to be different between the two groups during the 12 cycles of maintenance therapy (p = 0.49) (Figure 2), or from the end of maintenance (p = 0.38). Additionally, maintenance treatment with midostaurin did not significantly affect OS (p = 0.86).27 Given these findings, the role of midostaurin as maintenance therapy requires further investigation. Figure 2. View largeDownload slide Landmark analysis of disease-free survival (DFS) during the 12 cycles of maintenance, censoring patients at the time they completed the planned maintenance or discontinued study drug early. Reproduced from reference 27 with permission of American Society of Hematology. Figure 2. View largeDownload slide Landmark analysis of disease-free survival (DFS) during the 12 cycles of maintenance, censoring patients at the time they completed the planned maintenance or discontinued study drug early. Reproduced from reference 27 with permission of American Society of Hematology. AMS, SM-AHN, and MCL. Prior to midostaurin’s approval, advanced SM was commonly managed with cladribine and interferon alfa on the basis of findings from small, retrospective studies.28,29 Imatinib is an FDA-approved alternative for those with ASM without the KIT D816V mutation or those with unknown KIT D816V mutation status. Unfortunately, the KIT D816V mutation is observed in nearly 90% of patients with ASM, thus the role for imatinib in this population is limited.30 NCT00782067, the landmark trial for midostaurin in advanced SM, included 116 patients; 16 with ASM, 57 with SM-AHN, and 16 with MCL.31 Adults over the age of 18 years with an Eastern Cooperative Oncology Group performance status of 0 to 3 were included. Those with at least one measurable C-finding (i.e., clinical findings associated with organ damage from infiltrating mast cells) were eligible for the primary efficacy population. Patients received open-label midostaurin 100 mg twice daily in 4-week continuous cycles. The primary outcome assessed best overall response rates (ORRs) in the first six 4-week treatment cycles that were maintained for at least 8 weeks. Overall response was categorized based on the percentage of patients who achieved a major response (complete resolution of ≥ 1 C-finding) or a partial response. Partial response was broken down into good response (> 50% improvement in ≥1 C-finding) and minor response (> 20% to ≤ 50% improvement in ≥ 1 C-finding). A prespecified threshold of 30% overall response was established to be able to reject the null hypothesis.31 An ORR of 60% (95% confidence interval [CI], 49–70%; p < 0.001) was observed in the NCT00782067 trial, with 45% of those patients achieving a major response and 15% having a partial response.31 Among those who achieved a response, the median duration was 24.1 months. Median OS was 28.7 months in the primary efficacy population and progression-free survival was 14.1 months. In patients with MCL, the median OS was 9.4 months, nearly 3.5 months longer than observed with previous treatment modalities. Additionally, serum tryptase levels and bone marrow mast-cell burden decreased by > 50%. Ultimately, results of the NCT00782067 trial showed increased ORR regardless of SM subtype, KIT D816V mutation status, or history of prior therapy. Based on this data, midostaurin should be considered as first line therapy for advanced SM.31 Safety Many of the toxicities observed in the RATIFY trial are expected in patients receiving intensive chemotherapy regimens such as those used during the trial.26 The most common adverse reactions (≥ 20%) in the midostaurin group included febrile neutropenia, nausea, vomiting, mucositis, headache, petechiae, epistaxis, device-related infections, hyperglycemia, upper respiratory tract infections, and musculoskeletal pain.14 Overall the rates of grade 3, 4, and 5 adverse events were nearly identical between patients receiving midostaurin and placebo, with the exception of rash and anemia, which were significantly higher in the midostaurin group (Table 1). Adverse drug reactions led to treatment discontinuation in 9% and 6% of midostaurin and placebo recipients, respectively. There were no fatal adverse drug reactions in the RATIFY trial.14,26 Table 1. Summary of Common (≥ 20%) Grade 3, 4, or 5 Adverse Events Observed in the RATIFY Trial26 Adverse Event No. (%) Patients P Midostaurin Group (n = 355) Placebo Group (n = 354) Hematologic  Thrombocytopenia 346 (97) 342 (97) 0.52  Neutropenia 338 (95) 339 (96) 0.86  Anemia 329 (93) 311 (88) 0.03  Leukopenia 93 (26) 105 (30) 0.32  Lymphopenia 68 (19) 78 (22) 0.35 Nonhematologic  Febrile neutropenia 290 (82) 292 (82) 0.84  Infection 186 (52) 178 (50) 0.60 Adverse Event No. (%) Patients P Midostaurin Group (n = 355) Placebo Group (n = 354) Hematologic  Thrombocytopenia 346 (97) 342 (97) 0.52  Neutropenia 338 (95) 339 (96) 0.86  Anemia 329 (93) 311 (88) 0.03  Leukopenia 93 (26) 105 (30) 0.32  Lymphopenia 68 (19) 78 (22) 0.35 Nonhematologic  Febrile neutropenia 290 (82) 292 (82) 0.84  Infection 186 (52) 178 (50) 0.60 View Large Table 1. Summary of Common (≥ 20%) Grade 3, 4, or 5 Adverse Events Observed in the RATIFY Trial26 Adverse Event No. (%) Patients P Midostaurin Group (n = 355) Placebo Group (n = 354) Hematologic  Thrombocytopenia 346 (97) 342 (97) 0.52  Neutropenia 338 (95) 339 (96) 0.86  Anemia 329 (93) 311 (88) 0.03  Leukopenia 93 (26) 105 (30) 0.32  Lymphopenia 68 (19) 78 (22) 0.35 Nonhematologic  Febrile neutropenia 290 (82) 292 (82) 0.84  Infection 186 (52) 178 (50) 0.60 Adverse Event No. (%) Patients P Midostaurin Group (n = 355) Placebo Group (n = 354) Hematologic  Thrombocytopenia 346 (97) 342 (97) 0.52  Neutropenia 338 (95) 339 (96) 0.86  Anemia 329 (93) 311 (88) 0.03  Leukopenia 93 (26) 105 (30) 0.32  Lymphopenia 68 (19) 78 (22) 0.35 Nonhematologic  Febrile neutropenia 290 (82) 292 (82) 0.84  Infection 186 (52) 178 (50) 0.60 View Large In the NCT00782067 trial for advanced SM, ≥ 20% rates of grade 3 or 4 adverse events were much less common than those observed in the RATIFY trial: anemia (41%), neutropenia (24%), thrombocytopenia (29%). Other common adverse effects of any grade were nausea (79%), vomiting (66%), diarrhea (54%), peripheral edema (34%), abdominal pain (28%), fatigue (28%), pyrexia (27%), constipation (24%), headache (23%), and back pain (20%). In this trial, the dose of midostaurin had to be reduced in over half of patients, mostly owing to adverse events.31 Due to the roughly 80% frequency of nausea in patients receiving midostaurin during clinical trials, it is recommended to administer prophylactic antiemetics prior to treatment. When considering antiemetics, it is important to appreciate the small risk for QTc interval prolongation seen with midostaurin; therefore, QT interval assessments should be performed in patients taking concomitant QT interval prolonging medications.14 Additionally, it has been suggested that pulmonary toxicity may be associated with coadministration of potent CYP3A4 inhibitors, such as azole antifungals;26 therefore, patients should be evaluated on an individual basis when considering these agents. Cost Unfortunately, midostaurin is not exempt from the rising costs of cancer care. Midostaurin is currently supplied as 25-mg capsules and has an average wholesale price (AWP) of $160.61 per capsule.32 As previously stated, dosing is dependent upon indication for use. Patients with FLT3-mutated AML should receive 50 mg twice daily on days 8 to 21 of each induction and consolidation cycle; therefore, the acquisition cost for each 14-day course is expected to reach $9000. The dose of midostaurin for advanced SM is 100 mg twice daily and continued until disease progression or toxicity, which could amount to tens of thousands of dollars. While there are no pharmacoeconomic studies evaluating the cost of midostaurin, we believe it is currently the best alternative available and its use should be recommended for the above indications. Future directions Midostaurin is currently being investigated in nearly 30 clinical trials, most of which are in the AML population; Table 2 provides a list of some ongoing or completed trials.33 The RATIFY trial investigated midostaurin in patients aged 18–59 years with newly diagnosed, FLT3-mutated AML in combination with cytarabine and daunorubicin, thus leaving unanswered questions about its use in combination with other chemotherapy regimens, patients > 60 years of age and relapsed or refractory AML, which encompasses a large portion of the AML population. Within the next several years, we anticipate more data will become available to elucidate midostaurin’s role in this difficult-to-treat population. Table 2. Midostaurin Clinical Studiesa Phase Status Disease Therapeutic Agents I/II33 Active, not recruiting Untreated AML in elderly patients (NCT01093573) Midostaurin + azacitidine I34 Active, not recruiting Locally advanced rectal cancer (NCT01282502) Midostaurin I35 Completed Relapsed/refractory AML (NCT01174888) Midostaurin + bortezomib II36 Recruiting Newly diagnosed AML in older patients (NCT02634827) Midostaurin + decitabine I37 Completed Newly diagnosed or relapsed/refractory AML in patients age > 60 years (NCT01130662) Midostaurin + decitabine II38 Completed ASM and MCL (NCT00233454) Midostaurin Phase Status Disease Therapeutic Agents I/II33 Active, not recruiting Untreated AML in elderly patients (NCT01093573) Midostaurin + azacitidine I34 Active, not recruiting Locally advanced rectal cancer (NCT01282502) Midostaurin I35 Completed Relapsed/refractory AML (NCT01174888) Midostaurin + bortezomib II36 Recruiting Newly diagnosed AML in older patients (NCT02634827) Midostaurin + decitabine I37 Completed Newly diagnosed or relapsed/refractory AML in patients age > 60 years (NCT01130662) Midostaurin + decitabine II38 Completed ASM and MCL (NCT00233454) Midostaurin aAML = acute myeloid leukemia; ASM = aggressive systemic mastocytosis; MCL = mast cell leukemia. View Large Table 2. Midostaurin Clinical Studiesa Phase Status Disease Therapeutic Agents I/II33 Active, not recruiting Untreated AML in elderly patients (NCT01093573) Midostaurin + azacitidine I34 Active, not recruiting Locally advanced rectal cancer (NCT01282502) Midostaurin I35 Completed Relapsed/refractory AML (NCT01174888) Midostaurin + bortezomib II36 Recruiting Newly diagnosed AML in older patients (NCT02634827) Midostaurin + decitabine I37 Completed Newly diagnosed or relapsed/refractory AML in patients age > 60 years (NCT01130662) Midostaurin + decitabine II38 Completed ASM and MCL (NCT00233454) Midostaurin Phase Status Disease Therapeutic Agents I/II33 Active, not recruiting Untreated AML in elderly patients (NCT01093573) Midostaurin + azacitidine I34 Active, not recruiting Locally advanced rectal cancer (NCT01282502) Midostaurin I35 Completed Relapsed/refractory AML (NCT01174888) Midostaurin + bortezomib II36 Recruiting Newly diagnosed AML in older patients (NCT02634827) Midostaurin + decitabine I37 Completed Newly diagnosed or relapsed/refractory AML in patients age > 60 years (NCT01130662) Midostaurin + decitabine II38 Completed ASM and MCL (NCT00233454) Midostaurin aAML = acute myeloid leukemia; ASM = aggressive systemic mastocytosis; MCL = mast cell leukemia. View Large Unfortunately, resistance to FLT3 inhibitors is beginning to emerge, which may impact durability of response to these agents. Resistance is thought to occur by way of multiple mechanisms, including upregulation of downstream signaling pathways, increases in FLT3 ligands and receptors, and acquiring secondary tyrosine kinase domain point mutations.39,40 Pre-clinical studies have indicated that several newer agents (e.g., AMG 925, SAR302503, ponatinib, G-749) may play a role in overcoming FLT3 inhibitor resistance.41-44 Conclusion Midostaurin offers a novel strategy to treat both FLT3-mutated AML and advanced SM. With a comparable adverse effect profile to other agents and substantial antiproliferative activity, midostaurin offers a therapeutic option for patients who have historically been difficult to treat. Disclosures The authors have declared no potential conflicts of interest. References 1. National Cancer Institute . 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Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria . Leuk Res . 2003 ; 27 : 635 – 41 . Google Scholar Crossref Search ADS PubMed 17. Lim KH , Tefferi A , Lasho TL et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors . Blood . 2009 ; 113 : 5727 – 36 . Google Scholar Crossref Search ADS PubMed 18. Georgin-Lavialle S , Lhermitte L , Dubreuil P et al. Mast cell leukemia . Blood . 2013 ; 121 : 1285 – 95 . Google Scholar Crossref Search ADS PubMed 19. He H , Tran P , Gu H et al. Midostaurin, a novel protein kinase inhibitor for the treatment of acute myelogenous leukemia: insights from human absorption, metabolism, and excretion studies of a BDDCS II drug . Drug Metab Dispos . 2017 ; 45 : 540 – 55 . Google Scholar Crossref Search ADS PubMed 20. Dutreix C , Munarini F , Lorenzo S et al. Investigation into CYP3A4-mediated drug-drug interactions on midostaurin in healthy volunteers . Cancer Chemother Pharmacol . 2013 ; 72 : 1223 – 34 . Google Scholar Crossref Search ADS PubMed 21. Muppidi MR , Griffiths EA , Thompson JE et al. Decitabine and sorafenib therapy in patients with FLT3-ITD mutant acute myeloid leukemia is associated with high response rates—a single institute experience . Blood . 2014 ; 124 : 5284 . 22. 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 : 4655 – 62 . Google Scholar Crossref Search ADS PubMed 23. 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 ; 28 : 1856 – 62 . Google Scholar Crossref Search ADS PubMed 24. Röllig C , Brandts C , Shaid S et al. Survey and analysis of the efficacy and prescription pattern of sorafenib in patients with acute myeloid leukemia . Leuk Lymphoma . 2012 ; 53 : 1062 – 7 . Google Scholar Crossref Search ADS PubMed 25. 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 : 2061 – 8 . Google Scholar Crossref Search ADS PubMed 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 : 454 – 64 . Google Scholar Crossref Search ADS PubMed 27. Larson RA , Mandrekar SJ , Sanford BL et al. An analysis of maintenance therapy and post-midostaurin outcomes in the international prospective randomized, placebo-controlled, doubleblind trial (CALGB 10603/RATIFY [Alliance]) for newly diagnosed acute myeloid leukemia (AML) patients with FLT3 mutations . Oral presentation at: American Society of Hematology 59th Annual Meeting & Exposition . December 9–12, 2017 ; Atlanta, GA . 28. Delaporte E , Piérard E , Wolthers BG et al. Interferon-alpha in combination with corticosteroids improves systemic mast cell disease . Br J Dermatol . 1995 ; 132 : 479 – 82 . Google Scholar Crossref Search ADS PubMed 29. Kluin-Nelemans HC , Oldhoff JM , Van Doormaal JJ et al. Cladribine therapy for systemic mastocytosis . Blood . 2003 ; 102 : 4270 – 6 . Google Scholar Crossref Search ADS PubMed 30. Gleevec (imatinib mesylate) package insert. East Hanover, NJ : Novartis Pharmaceuticals Corporation ; 2015 Jan. 31. Gotlib J , Kluin-Nelemans HC , George TI et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis . N Engl J Med . 2016 ; 374 : 2530 – 41 . Google Scholar Crossref Search ADS PubMed 32. Midostaurin . Lexi-Drugs. Lexicomp . Wolters Kluwer Health, Inc . Riverwoods, IL . http://online.lexi.com. (accessed 2017 Sep 25 ). 33. National Pharmaceutical Services . 2017 . https://www.pti-nps.com/nps/index.php/drug-update-may-2017/ (accessed 2018 Dec 19) . 34. ClinicalTrials.gov . Midostaurin (PKC412) for locally advanced rectal cancer . http://clinicaltrials.gov/ct2/show/NCT01282502 (accessed 2017 Sep 25 ). 35. ClinicalTrials.gov . Phase I combination of midostaurin, bortezomib, and chemo in relapsed/refractory acute myeloid leukemia . http://clinicaltrials.gov/ct2/show/NCT01174888 (accessed 2017 Sep 25 ). 36. ClinicalTrials.gov . Midostaurin and decitabine in treating older patients with newly diagnosed acute myeloid leukemia and FLT3 mutation . http://clinicaltrials.gov/ct2/show/NCT02634827 (accessed 2017 Sep 25 ). 37. ClinicalTrials.gov . Combination of decitabine and midostaurin in patients older than 60 with newly diagnosed or relapsed refractory acute myeloid leukemiahttp://clinicaltrials.gov/ct2/show/NCT01130662 (accessed 2017 Sep 25 ). 38. ClinicalTrials.gov . Phase II midostaurin in aggressive systemic mastocytosis and mast cell leukemiahttp://clinicaltrials.gov/ct2/show/NCT00233454 (accessed 2017 Sep 25 ). 39. Weisberg E , Sattler M , Ray A , Griffin JD. Drug resistance in mutant FLT3-positive AML . Oncogene . 2010 ; 29 : 5120 – 34 . Google Scholar Crossref Search ADS PubMed 40. Hassanein M , Almahayni MH , Ahmed SO et al. FLT3 inhibitors for treating acute myeloid leukemia . Clin Lymphoma Myeloma Leuk . 2016 ; 16 : 543 – 9 . Google Scholar Crossref Search ADS PubMed 41. Li C , Liu L , Liang L et al. AMG 925 is a dual FLT3/CDK4 inhibitor with the potential to overcome FLT3 inhibitor resistance in acute myeloid leukemia . Mol Cancer Ther . 2015 ; 14 : 375 – 83 . Google Scholar Crossref Search ADS PubMed 42. Kesarwani M , Huber E , Azam M. Overcoming AC220 resistance of FLT3-ITD by SAR302503 . Blood Cancer J . 2013 ; 3 : e138 . Google Scholar Crossref Search ADS PubMed 43 Zirm E , Spies-Weisshart B , Heidel F et al. Ponatinib may overcome resistance of FLT3-ITD harbouring additional point mutations, notably the previously refractory F691I mutation . Br J Haematol . 2012 ; 157 : 483 – 92 . Google Scholar Crossref Search ADS PubMed 44. Lee HK , Kim HW , Lee IY et al. G-749, a novel FLT3 kinase inhibitor, can overcome drug resistance for the treatment of acute myeloid leukemia . Blood . 2014 ; 123 : 2209 – 19 . Google Scholar Crossref Search ADS PubMed © American Society of Health-System Pharmacists 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Health-System Pharmacy Oxford University Press

Midostaurin for the management of FLT3-mutated acute myeloid leukemia and advanced systemic mastocytosis

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Abstract

Abstract Purpose This article reviews the pharmacology, efficacy, safety, cost, and future directions of midostaurin for the treatment of acute myeloid leukemia (AML), aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm, and mast cell leukemia, collectively known as advanced systemic mastocytosis (SM). Summary Midostaurin was approved by the U.S. Food and Drug Administration for the treatment of FMS-like tyrosine kinase-3 (FLT3)- mutated AML. FLT3 is a tyrosine kinase which plays a key role in proliferation of early hematopoietic progenitor cells. In addition to having activity against FLT3, midostaurin inhibits several other tyrosine kinases which led to its approval for the treatment of advanced SM. Conclusion Midostaurin offers a novel strategy to treat both FLT3-mutated AML and advanced SM. With a comparable adverse effect profile to other agents and substantial antiproliferative activity, midostaurin offers a therapeutic option for patients who have historically been difficult to treat. antineoplastics, clinical pharmacology, leukemia, mastocytosis, oncology, pharmacokinetics KEY POINTS Midostaurin is the first agent approved for the treatment of FLT3-mutated acute myeloid leukemia (AML), and is the first new drug approved for AML since 2000. Midostaurin has been shown to be efficacious in both FLT3-ITD and FLT3-TKD mutated AML. Midostaurin inhibits several other tyrosine kinases in addition to FLT3, leading to its approval for the treatment of advanced systemic mastocytosis. Acute myeloid leukemia (AML) is the most common acute leukemia among adults, with an estimated 19,520 new cases in 2018, and accounts for the greatest number of deaths from leukemia in the United States.1 For nearly 40 years, the standard induction treatment for patients < 60 years of age has been cytarabine, given as a continuous infusion over 7 days, plus either daunorubicin or idarubicin administered daily for 3 days.2 Despite advancements in molecular profiling, AML remains difficult to treat, with an average 5-year survival rate of 27.4%.1 Cytogenetic and mutational data have allowed researchers to better predict prognostic factors and provide targetable treatment options with the potential to improve survival.3 One of the most well studied molecular markers in AML is the FMS-like tyrosine kinase-3 (FLT3). This tyrosine kinase plays a key role in proliferation of early hematopoietic progenitor cells.4 Activating mutations of the FLT3 gene on chromosome 13q12 are generally divided into 2 subgroups: internal tandem duplications (ITD) and a point mutation of the tyrosine kinase domain (TKD).5FLT3-ITD mutations are more common (found in approximately 23% of AML cases) and are correlated with shorter remission durations, leading to a reduction in overall survival (OS) when compared with FLT3 wild type.6-10 The prognostic implications of FLT3-TKD mutations (found in approximately 7% of AML cases) are less clear, with some reports suggesting that FLT3-TKD mutations have no impact on survival.8,11,12 Ultimately, the poor outcomes associated with FLT3-mutated AML led to the development of midostaurin (Rydapt, Novartis Pharmaceuticals Corporation, East Hanover, NJ), the first agent approved for the treatment of FLT3-mutated AML, and the first new drug approved for AML since 2000.13 Midostaurin is an oral small molecule, first-generation FLT3 inhibitor. In addition to inhibiting FLT3, midostaurin also has activity against KIT proto-oncogene receptor tyrosine kinase (KIT) (wild-type and D816V mutant), platelet-derived growth factor (PDGFR) α/β, vascular endothelial growth factor 2 (VEGFR2), and members of the serine/threonine kinase protein kinase C family. Because of its activity against these receptors, labeling for midostaurin was approved by the U.S. Food and Drug Administration (FDA) with indications for the treatment of aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL), collectively known as advanced systemic mastocytosis (SM).14 More than 80% of patients with advanced SM have a KIT D816V mutation, making midostaurin an effective medication for this indication.15 Advanced SM is a myeloid neoplasm caused by the accumulation of mast cells in organs such as the bone marrow, skeletal system, liver, spleen, and gastrointestinal tract. Symptoms of this disease are related to the organs affected by mast cell accumulation; it is common for these patients to develop cytopenia, osteolysis leading to fractures, hepatosplenomegaly, and weight loss, collectively referred to as C-findings.16 The prognosis for patients with advanced SM is generally quite poor, with expected survival time ranging from 3.5 years in patients diagnosed with ASM to a mere 6 months in patients with MCL.17,18 The recommended dosing of midostaurin differs based on indication for use. For newly diagnosed FLT3-mutated AML, the recommended dose of midostaurin is 50 mg orally taken twice daily with food on days 8–21 of induction chemotherapy with cytarabine and daunorubicin and again on days 8–21 of each consolidation cycle with high-dose cytarabine. The recommended dose of midostaurin for ASM, SM-AHN, or MCL is 100 mg orally taken twice daily with food until disease progression or unacceptable toxicity.14 In this article, we describe the pharmacology, efficacy, safety, cost, and future directions of midostaurin for the treatment of AML and advanced SM. Pharmacokinetics and pharmacodynamics Midostaurin is rapidly absorbed and reaches peak plasma concentrations within 1 to 3 hours post dose and is thought to have very high oral absorption (> 90%) based on the low levels of unchanged midostaurin found in the urine and feces (< 5%).19 Compared with a fasting state, the midostaurin area under the curve (AUC) is increased by 1.2-fold when given with a standard meal and 1.6-fold when given with a high-fat meal; because of these findings, it is recommended midostaurin be administered with food.14 Midostaurin appears to have a large volume of distribution (95.2 L), indicating high tissue distribution.14 Midostaurin is metabolized primarily through cytochrome P450 (CYP) isoenzyme 3A4 into two active metabolites, CGP62221 (via O-demethylation) and CGP52421 (via 7-hydroxylation).19 A recent study of healthy volunteers investigated the effects of midostaurin when given with ketoconazole and rifampin, potent CYP3A4 inhibitors and inducers, respectively. The influence of ketoconazole on midostaurin was significant, causing a 1.8-fold increase in the maximum concentration (C max) and a 10-fold increase in AUC due to decreased clearance of midostaurin. This was correlated with a higher frequency of nausea, dry skin, abdominal distension, cough, and sleep disorders when compared with placebo.20 As anticipated, CYP3A4 induction with rifampin had an opposing impact on midostaurin exposure; when given in combination with rifampin, the clearance of midostaurin increased 16.9-fold compared with placebo. Interestingly, both metabolites exhibited a similar pattern, indicating midostaurin and its metabolites are primarily cleared from the body via CYP3A4 metabolism. Efficacy data were not assessed. Given the extent of interaction with potent CYP3A4 inducers, concomitant use of midostaurin with strong or moderate inducers of CYP3A4 should be avoided.20 Midostaurin exhibits linear kinetics in the first 3 to 6 days after administration and shifts to time-dependent kinetics thereafter. This kinetic profile causes the plasma concentrations of midostaurin to decrease substantially between days 6 and 14 with steady state being reached after approximately 28 days. CGP62221 exhibits a similar pharmacokinetic profile to the parent compound, while CGP52421 plasma concentrations continue to rise following 1 month of treatment.14,20 As previously mentioned, the coadministration of midostaurin with strong CYP3A4 inhibitors may lead to increased midostaurin concentrations and consequently increased toxicities; these effects are thought to be more pronounced during the first week of therapy due to the initial phase of linear kinetics. The terminal half-life of midostaurin is nearly 21 hours, similar to CGP62221 (32 hours), but much shorter than that of CGP52421 (482 hours). Midostaurin and its metabolites are greater than 99.8% protein bound to α-1-acid glycoprotein, which may contribute to its long half-life.14 Factors such as age, sex, and mild or moderate hepatic and renal impairment have not been shown to have a clinically meaningful impact on the pharmacokinetics of midostaurin. Unfortunately, data are lacking in patients with severe hepatic impairment (total bilirubin level > 3 times the upper limit of normal and any aspartate aminotransferase [AST] above the upper limit of normal) or severe renal impairment (creatinine clearance [CLCr] of 15 to 30 mL/minute); thus, use in this patient population is not recommended.14 Efficacy AML. Historically, patients with FLT3-mutated AML had the option of being treated off-label with regimens such as decitabine and sorafenib;21 azacitidine and sorafenib;22 or idarubicin, cytarabine, and sorafenib.23 Sorafenib, like midostaurin, is a multiple kinase inhibitor with activity against FLT3 mutations. Although some patients have achieved clinical remission with sorafenib, responses are often short-lived, which prompted the investigation of midostaurin for this indication.24 A Phase IB trial (NCT0093600) was among the first to investigate the use of midostaurin for AML. Newly diagnosed patients with mutated and wild-type FLT3 AML were assigned to receive midostaurin in combination with daunorubicin and cytarabine induction therapy followed by high-dose cytarabine consolidation therapy. Patients receiving midostaurin 50 mg twice daily demonstrated high complete response (CR) rates of 80%, (74% in FLT3-wild type and 92% in FLT3-mutant AML). Of note, this study was initially designed using midostaurin 100 mg twice daily, but due to high rates of grade 3 and 4 nausea and vomiting, the dosing schedule was modified to 50 mg twice daily.25 The results from this early study provided the clinical groundwork for the CALGB 10603 (RATIFY) trial.26 The landmark RATIFY trial that led to midostaurin’s approval for AML, included 717 patients between 18 and 59 years of age with newly diagnosed FLT3-mutated AML. Once confirmation of the FLT3 mutation was obtained, patients were randomized to receive standard chemotherapy (cytarabine 200 mg/m2 given as a continuous infusion for 7 days, plus daunorubicin 60 mg/m2 administered on days 1 to 3) in combination with either midostaurin 50 mg twice daily on days 8 to 21 or placebo for up to 2 cycles of induction. Patients who achieved CR after induction therapy received four 28-day cycles of consolidation therapy with high-dose cytarabine 3000 mg/m2 every 12 hours on days 1, 3, and 5 and either placebo or midostaurin 50 mg twice daily on days 8 to 21. Those who maintained remission after consolidation therapy entered a maintenance phase where they received placebo or midostaurin 50 mg twice daily for 12 months.26 Patients were stratified according to the subtype of FLT3 mutation: TKD or ITD with either a high ratio (> 0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles. FLT3 subtype was ITD (high) in 29.8% of patients, ITD (low) 47.6% of patients, and TKD in 22.6% of patients. After the minimum follow-up duration of 3.5 years following randomization, OS was significantly longer in the midostaurin group compared with placebo (hazard ratio [HR] 0.78: OS, 74.7 months vs. 25.6 months; p = 0.009). The 4-year median OS rate was 51.4% in the midostaurin group compared with 44.3% in the placebo group. Median disease-free survival (DFS) was also improved in the midostaurin group (26.7 months vs. 15.5 months; p = 0.01). A total of 57% of patients underwent stem cell transplantation (SCT) at some point during their disease course, with 28.1% undergoing SCT during first complete remission (CR1) in the midostaurin group and 22.7% in the placebo group (p = 0.10). First complete remission was defined as the presence of less than 5% blasts in the marrow or extramedullary leukemia, an absolute neutrophil count of more than 1000 per microliter, a platelet count of more than 100,000 per microliter, and the absence of blasts in the peripheral blood. Additionally, the complete remission had to have occurred by day 60. Ultimately, results of the trial demonstrated patients receiving midostaurin for newly diagnosed FLT3-mutated AML had better median OS, event free survival, and DFS when compared with placebo.26 The results of the RATIFY trial revealed several important findings. First, no significant difference was found upon analysis of subgroups according to their FLT3 subtype. Given the prognostic implications of FLT-ITD and FLT-TKD mutations, it is theorized that patients with FLT-ITD high disease would benefit most from treatment with midostaurin, but in fact patients with FLT3-TKD mutations had the lowest OS hazard ratio (HR = 0.65).26 This finding, combined with the results from the Phase IB trial suggests that at least some component of midostaurin’s efficacy comes from its multitargeted mechanism of action. Another important finding from the RATIFY trial is that the survival curves between midostaurin and placebo separated quickly (Figure 1), suggesting benefit from midostaurin occurs early in the treatment course. This is consistent with midostaurin’s pharmacokinetic profile in which plasma concentrations are the highest during the first month of treatment.14,20 Figure 1. View largeDownload slide Kaplan–Meier curves for median overall survival in the midostaurin group and the placebo group in the RATIFY trial. Tick marks indicate censoring of data. From New Engl J Med, Stone RM, Mandrekar SJ, Sanford BL et al., Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation, 377, 454-64. Copyright © 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Figure 1. View largeDownload slide Kaplan–Meier curves for median overall survival in the midostaurin group and the placebo group in the RATIFY trial. Tick marks indicate censoring of data. From New Engl J Med, Stone RM, Mandrekar SJ, Sanford BL et al., Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation, 377, 454-64. Copyright © 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. A post-hoc analysis of the RATIFY trial was recently conducted by Larson and colleagues27 to investigate a subset of patients achieving CR that were subsequently started on maintenance therapy. This analysis included 105 patients receiving maintenance therapy with midostaurin and 69 patients receiving placebo. Surprisingly, DFS was not found to be different between the two groups during the 12 cycles of maintenance therapy (p = 0.49) (Figure 2), or from the end of maintenance (p = 0.38). Additionally, maintenance treatment with midostaurin did not significantly affect OS (p = 0.86).27 Given these findings, the role of midostaurin as maintenance therapy requires further investigation. Figure 2. View largeDownload slide Landmark analysis of disease-free survival (DFS) during the 12 cycles of maintenance, censoring patients at the time they completed the planned maintenance or discontinued study drug early. Reproduced from reference 27 with permission of American Society of Hematology. Figure 2. View largeDownload slide Landmark analysis of disease-free survival (DFS) during the 12 cycles of maintenance, censoring patients at the time they completed the planned maintenance or discontinued study drug early. Reproduced from reference 27 with permission of American Society of Hematology. AMS, SM-AHN, and MCL. Prior to midostaurin’s approval, advanced SM was commonly managed with cladribine and interferon alfa on the basis of findings from small, retrospective studies.28,29 Imatinib is an FDA-approved alternative for those with ASM without the KIT D816V mutation or those with unknown KIT D816V mutation status. Unfortunately, the KIT D816V mutation is observed in nearly 90% of patients with ASM, thus the role for imatinib in this population is limited.30 NCT00782067, the landmark trial for midostaurin in advanced SM, included 116 patients; 16 with ASM, 57 with SM-AHN, and 16 with MCL.31 Adults over the age of 18 years with an Eastern Cooperative Oncology Group performance status of 0 to 3 were included. Those with at least one measurable C-finding (i.e., clinical findings associated with organ damage from infiltrating mast cells) were eligible for the primary efficacy population. Patients received open-label midostaurin 100 mg twice daily in 4-week continuous cycles. The primary outcome assessed best overall response rates (ORRs) in the first six 4-week treatment cycles that were maintained for at least 8 weeks. Overall response was categorized based on the percentage of patients who achieved a major response (complete resolution of ≥ 1 C-finding) or a partial response. Partial response was broken down into good response (> 50% improvement in ≥1 C-finding) and minor response (> 20% to ≤ 50% improvement in ≥ 1 C-finding). A prespecified threshold of 30% overall response was established to be able to reject the null hypothesis.31 An ORR of 60% (95% confidence interval [CI], 49–70%; p < 0.001) was observed in the NCT00782067 trial, with 45% of those patients achieving a major response and 15% having a partial response.31 Among those who achieved a response, the median duration was 24.1 months. Median OS was 28.7 months in the primary efficacy population and progression-free survival was 14.1 months. In patients with MCL, the median OS was 9.4 months, nearly 3.5 months longer than observed with previous treatment modalities. Additionally, serum tryptase levels and bone marrow mast-cell burden decreased by > 50%. Ultimately, results of the NCT00782067 trial showed increased ORR regardless of SM subtype, KIT D816V mutation status, or history of prior therapy. Based on this data, midostaurin should be considered as first line therapy for advanced SM.31 Safety Many of the toxicities observed in the RATIFY trial are expected in patients receiving intensive chemotherapy regimens such as those used during the trial.26 The most common adverse reactions (≥ 20%) in the midostaurin group included febrile neutropenia, nausea, vomiting, mucositis, headache, petechiae, epistaxis, device-related infections, hyperglycemia, upper respiratory tract infections, and musculoskeletal pain.14 Overall the rates of grade 3, 4, and 5 adverse events were nearly identical between patients receiving midostaurin and placebo, with the exception of rash and anemia, which were significantly higher in the midostaurin group (Table 1). Adverse drug reactions led to treatment discontinuation in 9% and 6% of midostaurin and placebo recipients, respectively. There were no fatal adverse drug reactions in the RATIFY trial.14,26 Table 1. Summary of Common (≥ 20%) Grade 3, 4, or 5 Adverse Events Observed in the RATIFY Trial26 Adverse Event No. (%) Patients P Midostaurin Group (n = 355) Placebo Group (n = 354) Hematologic  Thrombocytopenia 346 (97) 342 (97) 0.52  Neutropenia 338 (95) 339 (96) 0.86  Anemia 329 (93) 311 (88) 0.03  Leukopenia 93 (26) 105 (30) 0.32  Lymphopenia 68 (19) 78 (22) 0.35 Nonhematologic  Febrile neutropenia 290 (82) 292 (82) 0.84  Infection 186 (52) 178 (50) 0.60 Adverse Event No. (%) Patients P Midostaurin Group (n = 355) Placebo Group (n = 354) Hematologic  Thrombocytopenia 346 (97) 342 (97) 0.52  Neutropenia 338 (95) 339 (96) 0.86  Anemia 329 (93) 311 (88) 0.03  Leukopenia 93 (26) 105 (30) 0.32  Lymphopenia 68 (19) 78 (22) 0.35 Nonhematologic  Febrile neutropenia 290 (82) 292 (82) 0.84  Infection 186 (52) 178 (50) 0.60 View Large Table 1. Summary of Common (≥ 20%) Grade 3, 4, or 5 Adverse Events Observed in the RATIFY Trial26 Adverse Event No. (%) Patients P Midostaurin Group (n = 355) Placebo Group (n = 354) Hematologic  Thrombocytopenia 346 (97) 342 (97) 0.52  Neutropenia 338 (95) 339 (96) 0.86  Anemia 329 (93) 311 (88) 0.03  Leukopenia 93 (26) 105 (30) 0.32  Lymphopenia 68 (19) 78 (22) 0.35 Nonhematologic  Febrile neutropenia 290 (82) 292 (82) 0.84  Infection 186 (52) 178 (50) 0.60 Adverse Event No. (%) Patients P Midostaurin Group (n = 355) Placebo Group (n = 354) Hematologic  Thrombocytopenia 346 (97) 342 (97) 0.52  Neutropenia 338 (95) 339 (96) 0.86  Anemia 329 (93) 311 (88) 0.03  Leukopenia 93 (26) 105 (30) 0.32  Lymphopenia 68 (19) 78 (22) 0.35 Nonhematologic  Febrile neutropenia 290 (82) 292 (82) 0.84  Infection 186 (52) 178 (50) 0.60 View Large In the NCT00782067 trial for advanced SM, ≥ 20% rates of grade 3 or 4 adverse events were much less common than those observed in the RATIFY trial: anemia (41%), neutropenia (24%), thrombocytopenia (29%). Other common adverse effects of any grade were nausea (79%), vomiting (66%), diarrhea (54%), peripheral edema (34%), abdominal pain (28%), fatigue (28%), pyrexia (27%), constipation (24%), headache (23%), and back pain (20%). In this trial, the dose of midostaurin had to be reduced in over half of patients, mostly owing to adverse events.31 Due to the roughly 80% frequency of nausea in patients receiving midostaurin during clinical trials, it is recommended to administer prophylactic antiemetics prior to treatment. When considering antiemetics, it is important to appreciate the small risk for QTc interval prolongation seen with midostaurin; therefore, QT interval assessments should be performed in patients taking concomitant QT interval prolonging medications.14 Additionally, it has been suggested that pulmonary toxicity may be associated with coadministration of potent CYP3A4 inhibitors, such as azole antifungals;26 therefore, patients should be evaluated on an individual basis when considering these agents. Cost Unfortunately, midostaurin is not exempt from the rising costs of cancer care. Midostaurin is currently supplied as 25-mg capsules and has an average wholesale price (AWP) of $160.61 per capsule.32 As previously stated, dosing is dependent upon indication for use. Patients with FLT3-mutated AML should receive 50 mg twice daily on days 8 to 21 of each induction and consolidation cycle; therefore, the acquisition cost for each 14-day course is expected to reach $9000. The dose of midostaurin for advanced SM is 100 mg twice daily and continued until disease progression or toxicity, which could amount to tens of thousands of dollars. While there are no pharmacoeconomic studies evaluating the cost of midostaurin, we believe it is currently the best alternative available and its use should be recommended for the above indications. Future directions Midostaurin is currently being investigated in nearly 30 clinical trials, most of which are in the AML population; Table 2 provides a list of some ongoing or completed trials.33 The RATIFY trial investigated midostaurin in patients aged 18–59 years with newly diagnosed, FLT3-mutated AML in combination with cytarabine and daunorubicin, thus leaving unanswered questions about its use in combination with other chemotherapy regimens, patients > 60 years of age and relapsed or refractory AML, which encompasses a large portion of the AML population. Within the next several years, we anticipate more data will become available to elucidate midostaurin’s role in this difficult-to-treat population. Table 2. Midostaurin Clinical Studiesa Phase Status Disease Therapeutic Agents I/II33 Active, not recruiting Untreated AML in elderly patients (NCT01093573) Midostaurin + azacitidine I34 Active, not recruiting Locally advanced rectal cancer (NCT01282502) Midostaurin I35 Completed Relapsed/refractory AML (NCT01174888) Midostaurin + bortezomib II36 Recruiting Newly diagnosed AML in older patients (NCT02634827) Midostaurin + decitabine I37 Completed Newly diagnosed or relapsed/refractory AML in patients age > 60 years (NCT01130662) Midostaurin + decitabine II38 Completed ASM and MCL (NCT00233454) Midostaurin Phase Status Disease Therapeutic Agents I/II33 Active, not recruiting Untreated AML in elderly patients (NCT01093573) Midostaurin + azacitidine I34 Active, not recruiting Locally advanced rectal cancer (NCT01282502) Midostaurin I35 Completed Relapsed/refractory AML (NCT01174888) Midostaurin + bortezomib II36 Recruiting Newly diagnosed AML in older patients (NCT02634827) Midostaurin + decitabine I37 Completed Newly diagnosed or relapsed/refractory AML in patients age > 60 years (NCT01130662) Midostaurin + decitabine II38 Completed ASM and MCL (NCT00233454) Midostaurin aAML = acute myeloid leukemia; ASM = aggressive systemic mastocytosis; MCL = mast cell leukemia. View Large Table 2. Midostaurin Clinical Studiesa Phase Status Disease Therapeutic Agents I/II33 Active, not recruiting Untreated AML in elderly patients (NCT01093573) Midostaurin + azacitidine I34 Active, not recruiting Locally advanced rectal cancer (NCT01282502) Midostaurin I35 Completed Relapsed/refractory AML (NCT01174888) Midostaurin + bortezomib II36 Recruiting Newly diagnosed AML in older patients (NCT02634827) Midostaurin + decitabine I37 Completed Newly diagnosed or relapsed/refractory AML in patients age > 60 years (NCT01130662) Midostaurin + decitabine II38 Completed ASM and MCL (NCT00233454) Midostaurin Phase Status Disease Therapeutic Agents I/II33 Active, not recruiting Untreated AML in elderly patients (NCT01093573) Midostaurin + azacitidine I34 Active, not recruiting Locally advanced rectal cancer (NCT01282502) Midostaurin I35 Completed Relapsed/refractory AML (NCT01174888) Midostaurin + bortezomib II36 Recruiting Newly diagnosed AML in older patients (NCT02634827) Midostaurin + decitabine I37 Completed Newly diagnosed or relapsed/refractory AML in patients age > 60 years (NCT01130662) Midostaurin + decitabine II38 Completed ASM and MCL (NCT00233454) Midostaurin aAML = acute myeloid leukemia; ASM = aggressive systemic mastocytosis; MCL = mast cell leukemia. 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Journal

American Journal of Health-System Pharmacy – Oxford University Press

Published: Feb 9, 2019

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