Concurrent versus sequential or no triazole anti-fungal therapy in patients undergoing 7 + 3 plus midostaurin induction for FLT-3 acute myelogenous leukemia

Abstract

Introduction

Midostaurin is a multikinase inhibitor approved for the treatment of adult patients with newly diagnosed FMS-like tyrosine kinase 3 mutated (FLT3m) acute myeloid leukemia (AML). Azole antifungal medications are commonly used in AML and are known to interact with anti-cancer drugs such as midostaurin through the CYP3A pathway. However, there are no midostaurin related dose modifications recommended with strong CYP3A inhibitors.

Methods

We retrospectively reviewed 40 patients between 2017–2022 and compared efficacy and safety outcomes in patients who received azole antifungals concurrently to those who did not receive an azole or received it sequentially to midostaurin for treatment of FLT3m AML.

Results

Median age of both groups was approximately 55 years and 70% of patients harbored FLT-3 internal tandem duplication mutations. Most patients in the concurrent arm were on either posaconazole (33%) or isavuconazole (50%) for antifungal prophylaxis and micafungin (72%) for the sequential/no azole arm. Overall CR/CRi rate with concurrent versus sequential/no azole were 72% and 77%, and non-hematologic grade 3 toxicities were 22% and 40% (p = 0.21), respectively. Rates of dose reductions (6% vs. 0%, p = 0.26) and held doses (17% vs. 14%, p = 0.79) were not different between concurrent and sequential/no azole. There were no differences in the rates of new fungal infection during induction between the two groups.

Conclusion

Azoles given concurrently or sequentially with midostaurin were found to be equally safe and effective in the treatment of newly diagnosed FLT3 AML. Additional confirmatory studies are needed due to our limited sample size.

Keywords

Acute myeloid leukemia FLT3 inhibitors midostaurin

Introduction

Mutations of the FMS-like tyrosine kinase 3 (FLT3) have been reported in about a third of acute myeloid leukemia (AML) patients, with FLT3 mutations typically manifesting as either internal tandem duplication (ITD) or tyrosine kinase domain.¹ FLT3 is a tyrosine kinase receptor that is commonly expressed in hematopoietic stem cells that promotes proliferation and survival via proteins such as STAT5, AKT, and ERK and have been found expressed on AML blasts.² Patients with FLT3-ITD mutations often have a poor prognosis due to higher rates of relapse and a shorter median overall survival (OS) from the time of diagnosis.^1,3,4 The consensus is that a cure in FLT3m AML can only be achieved by obtaining remission and then consolidating with hematopoietic stem cell transplantation.^1,2 Midostaurin was the first FLT3 inhibitor to be approved by the Food and Drug Administration (FDA) for the treatment of FLT3m AML in combination with 7 + 3 induction.⁵ In the phase 3 placebo-controlled Cancer and Leukemia Group B (CALGB) 10603/RATIFY trial, the addition to midostaurin to intensive chemotherapy significantly improved overall survival (OS) and event-free survival.⁶ Midostaurin was well tolerated with the most common Grade 3 or higher adverse events (AEs) being febrile neutropenia (82%), infection (52%), lymphopenia (19%), and diarrhea (16%). There are some significant non-hematologic AEs associated with midostaurin, most notably QT prolongation and hepatotoxicity, that can cause significant morbidity and lead to delays in therapy.

Midostaurin is primarily metabolized via CYP3A4 leading to a manufacturer recommendation to avoid concomitant use of midostaurin and strong CYP3A4 inducers or inhibitors, and to consider alternative therapies.⁷ Pharmacokinetics studies of the coadministration of ketoconazole (a strong CYP3A4 inhibitor) with a single dose of midostaurin 50 mg increased the AUC_inf of midostaurin by 10.4 and its metabolite CGP6221 by 3.5-fold compared to a single midostaurin dose administered with placebo. Coadministration of itraconazole with multiple doses of midostaurin (100 mg twice daily on days 1 to 2 and 50 mg twice daily on days 3 to 28) increased Day 28 C_min concentrations of midostaurin by 2.1-fold, and the active metabolite CGP62221 by 1.2-fold compared to midostaurin alone. In the initial phase I extension study, there were reports of two cases of Grade 4 pulmonary edema and/or infiltrates in patients who were on antifungal azole medications known to be potent CYP3A4 inhibitors. Thereafter, enrollment of patients receiving azoles was suspended and a clear chest X-ray was made a part of the inclusion criteria. However, a retrospective sub-analysis of the RATIFY trial showed no significant increase in midostaurin related AEs in patients receiving strong CYP3A4 inhibitors.⁸ This exposure safety analysis showed a slightly shorter time to occurrence of Grade 3 or 4 clinically notable AEs with higher midostaurin and CPG6221 exposure. Azole antifungals with potent activity against molds, mainly aspergillus, should be strongly considered in patients with AML for prevention based on a study published by Cornely et al., where posaconazole was superior to fluconazole or itraconazole.^9,10 It remains unclear the clinical relevance of the interaction between azole antifungals and midostaurin during AML induction. At our institution, the choice of antifungal prophylaxis is not consistent, as some physicians have decided to not use azole antifungal or hold its use while on midostaurin due to concerns of increased toxicity. Therefore, we performed a retrospective review of our patients who received concurrent vs sequential or no azole antifungals in combination with midostaurin during AML induction.

Methods

We conducted a retrospective analysis of patients who received midostaurin in combination with intensive chemotherapy (7 + 3) per the RATIFY/CALGB 10603 investigators at City of Hope Medical Center (COH) between the period of December 2017 to November 2022. The study was approved by our COH institutional review board. Patients were identified using our electronic medical record using an ICD-10 code for AML and documented administration of all three medications in our medication administration records or outpatient prescriptions for both midostaurin. Inclusion criteria for the study were patients having received treatment COH and age of 18 years or older. Patients were excluded if they did not meet the inclusion criteria. Concurrent azole therapy was defined as a patient receiving azole antifungal therapy with midostaurin for more than 70% of the midostaurin doses. Sequential azole therapy was defined as patients receiving azole antifungal therapy with midostaurin for less than <70% of the doses and no azole antifungal therapy were patients who did not receive any azole doses with midostaurin therapy. Primary outcome of this study was rate of CR/CRi, where complete remission was defined as bone marrow blasts <5%; absence of circulating blasts; absence of extramedullary disease. Hematologic recovery was defined as absolute neutrophils count (ANC) ≥ 1000/mL and platelet count >100,000/mL.¹¹ Morphologic Leukemia-Free State (MLFS) is defined as absence of both bone marrow blasts <5% and extramedullary disease with no hematologic recovery required. Minimal residual disease (MRD) was obtained by flow cytometry. Secondary outcomes included: 6-month OS and a safety analysis comprised of incidence of new fungal infections (patients with prior fungal infections were excluded from this analysis) and rates of hepatotoxicity, cardiotoxicity (including QT prolongation), and other Grade 3 or 4 AEs. The grading of each AE was performed using the Common Terminology Criteria for Adverse Events version 5.0. We recorded fungal infections as per European Organization for Research and Treatment of Cancer/Mycoses Study Group definitions (EORTC).

Patients at our institution received an anthracycline of daunorubicin 60 mg/m² or idarubicin at 12 mg/m² for 3 days and 7-day continuous infusion cytarabine at 200 mg/m². The midostaurin was dosed at 50 mg orally twice daily on Days 8–21.

Results

There were 40 AML patients identified that received 7 + 3 + midostaurin for newly diagnosed FLT3 AML. Baseline demographics are summarized in Table 1.

Table 1.

Baseline characteristics.

	Concurrent Azole (n = 18)	Sequential or No Azole(n = 22)	p-value
Gender, n (%)
Male	9 (50)	11 (50)	1
Median age, yrs (range)	54.5 (26–75)	55.5 (28–71)	0.71
AML Type, n (%)
De-Novo	17 (94)	20 (91)	0.67
s-AML or t-AML	1 (6)	2 (9)	0.67
FLT3 Mutation, n (%)
ITD	13 (72)	16 (73)	0.97
TKD	5 (28)	6 (27)	0.97
NPM1 Mutation, n (%)
YES	6 (33)	11 (50)	0.29
NO	10 (56)	0 (0)	0.11
NA	2 (11)	11 (50)	0.73
Median blasts on BM biopsy, % (range)	65% (40–95)	70% (0–95)	0.21
Median WBC on presentation,	22.2 (0.7–177)	38 (0.6–303)	0.31
n (range)	37% (2–95)	47% (2–90)	0.88
Median peripheral blasts, % (range)
Antifungal used during treatment, n (%)
Posaconazole	6 (33)	5 (23)	0.45
Isavuconazole	9 (50)	0 (0)	<0.01
Fluconazole	3 (17)	0 (0)	0.046
Voriconazole	0 (0)	1 (5)	0.36
Micafungin	0 (0)	16 (72)	<0.01

AML: acute myeloid leukemia; ITD: internal tandem duplication; TKD: tyrosine kinase domain.

Most of our patients in both the concurrent and no azole groups were de novo newly diagnosed AML patients with FLT3 mutation status predominantly being the ITD subtype. Many of the patients received isavuconazole as the anti-fungal of choice while on induction therapy in the concurrent group.

Primary and secondary outcomes are summarized in Table 2. The combined rate of CR/CRi and MLFS was in the concurrent and sequential/no azole group was 72% and 77% with a MRD-positive incidence of 33% and 18% (p = 0.27), respectively. Median days to ANC and platelet recovery was 27 and 28 days in the concurrent, and 29 and 32 days in the sequential/no azole group. There were 72% and 68% of patients in the concurrent and sequential/no azole group who were able to proceed to allogenic stem cell transplant.

Table 2.

Outcomes of 7 + 3 with midostaurin for newly diagnosed FLT3 AML with concurrent or sequential azole.

	Concurrent Azole (n = 18)	Sequential or No Azole(n = 22)	p-value
Response to treatment, n (%)
CR/CRi/MLFS with MRD negative	7 (39)	13 (59)	0.2
CR/CRi/MLFS with MRD positive	6 (33)	4 (18)	0.27
Partial response or Persistent Disease	5 (28)	4 (18)	0.47
Not evaluable	0 (0)	1 (5)	0.36
Hematologic count recovery
Median days to ANC recovery (Range)	27 (26–84)	29 (26–63)	0.98
Median days to platelet recovery (Range)	28 (23–84)	32 (23–63)	0.67
Consolidate with HCT, n (%)	13 (72)	15 (68)	0.78
6-month survival rate, rate (95% CI)	0.85 (0.72–1.00)	0.87 (0.71–1.00)	0.95
Median follow-up, days (range)	244 (21–1637)	577 (42–1839)	0.24

AML: acute myeloid leukemia; ANC: absolute neutrophils count; HCT: hematopoietic stem cell transplantation; MLFS: Morphologic Leukemia-Free State; MRD: Minimal residual disease.

Table 3.

Safety analysis of 7 + 3 with midostaurin for newly diagnosed FLT3 AML with concurrent, sequential, or no azole.

	Concurrent Azole (n = 18)	Sequential or No Azole(n = 22)	p-value
Incidence of non-hematologic Grade 3 or 4 adverse event, n (%)	4 (22)	9 (40)	0.21
Cardiac Disorders	2 (11)	4 (18)
Transaminitis	1 (5.5)	1 (4.5)
Rash	1 (5.5)	0 (0)
Hyperbilirubinemia	0 (0)	3 (14)
Acute Kidney Injury	0 (0)	1 (4.5)
Midostaurin dose reduced, n (%)	1 (6)	0 (0)	0.26
Midostaurin dose held, n (%)	3 (17)	3 (14)	0.79
Hepatotoxicity, n (%)
Transaminitis	4 (22)	4 (18)	0.75
Hyperbilirubinemia	2 (11)	5 (23)	0.34
Cardiac Disorders, n(%)	3 (17)	5 (23)	0.63
Pulmonary Toxicities	0 (0)	0 (0)	NA
Incidence of new invasive fungal infection during induction, n (%)	5 (28)	4 (18)	0.47
30-day mortality, n (%)	1 (6)	0 (0)	0.26
90-day mortality, n (%)	1 (6)	2 (9)	0.67

AML, acute myeloid leukemia.

Regarding safety, which is summarized in Table 3, the incidence of grade 3 or 4 non-hematologic AEs was 22% and 40% respectively (p = 0.21). There were four incidences in the concurrent group who experienced Grade 3 or 4 AEs, which included cardiac disorders, transaminase elevation, and dermatologic toxicities. There were nine incidences in the sequential/no azole group who experienced Grade 3 or 4 AEs, which included cardiac disorders, hyperbilirubinemia, transaminase elevation, dermatologic toxicities, and creatinine increases. No cases of pulmonary toxicities were reported or grade 5 toxicities in either group. Though the incidence of grade 3 or 4 non-hematologic AEs were higher in the sequential/no azole group, the difference was found to be statistically not significant.

Hematologic recovery and the rate of new invasive fungal infection during induction therapy was similar between groups, with a mortality rate at 90-days that was 6% and 9% respectively. EORTC diagnosis criteria between cohorts were similar; proven (n = 1 vs n = 1), probable (n = 3 vs n = 0), and possible (n = 2 vs n = 3), respectively. Many of these cases were aspergillus fungal infections between cohorts (n = 4 vs n = 3), respectively. The 6-month overall survival between groups was 89% and 86% respectively, with the cause of deaths being sepsis and refractory disease in the concurrent group and the no azole group being cardiogenic shock, progression, and infection.

Discussion

There are currently no definitive recommendations on how to approach antifungal prophylaxis when utilizing midostaurin in combination with 7 + 3 in newly diagnosed AML. The European Hematology Association has suggested that posaconazole be used in conjunction with midostaurin but acknowledges that there is limited information to support this decision.¹² As reported in the RATIFY subgroup analysis, 214 patients who received midostaurin were on a strong CYP3A4 inhibitor and there were no clinically relevant differences in safety when compared to those without the interaction.⁸ The authors did report that patients who were on CYP3A4 inhibitors had higher incidence of severe infection and shorter median time to first Grade 3/4 clinically notable AEs, but no statistical analysis was performed to determine if they were significant. There were a few items missing from the analysis that would have made their conclusions more effective. Notable toxicities associated with midostaurin like QT prolongation and incidence of invasive fungal infections were not reported. In addition, some have questioned if an empiric dose adjustment is required when using an azole with strong CYP3A4 inhibition to prevent supratherapeutic levels of midostaurin, and this was not addressed in their study.¹³

Our retrospective study provides a comparison of different approaches to antifungal prophylaxis with midostaurin. Due to these concerns of toxicities, we demonstrated that using an echinocandin like micafungin while a patient receives intensive chemotherapy and midostaurin proved to be as effective in preventing invasive fungal infections as using an azole throughout the whole course of treatment, while maintaining similar remission rates. In our study, there was a higher incidence of Grade 3/4 AEs rates in the sequential/no azole group, but these were found not to be clinically significant and did not affect 30-day or 90-day mortality rates. Currently, there are no studies that compare different antifungal strategies with midostaurin. Rausch et al. did report on a similar approach with venetoclax where 58% of patients received an echinocandin prior to initiating an azole and determined that exposure to echinocandin did not affect breakthrough fungal infection rates.¹⁴ Their study concluded that neutrophil recovery and CR rates had the most significant impact on the incidence of breakthrough fungal infection. This emphasizes the point that patients at highest risk for fungal infections are those who experience prolonged and profound neutropenia, and these patients are ones that should be considered for a mold-active azole earlier on in treatment, given the lack of mold coverage that echinocandins have as monotherapy.¹⁵ All the patients in our study who had invasive fungal infections experienced issues with count recovery.

There were limitations to our study, mainly due to the small sample size and retrospective nature of study introducing the possibility of selection bias. In addition, we had sought out to determine if choice of azole based on the magnitude of CYP3A4 inhibition would impact efficacy and safety outcomes, but our small sample size prevented us from performing a more detailed analysis. Even with these limitations, our study does provide some clarity to the approach of azoles with midostaurin in newly diagnosed AML.

Conclusion

Footnotes

Author contributions

Dat Ngo: (1) the conception and design of the study, or acquisition of data, or analysis and interpretation of data, (2) drafting the article or revising it critically for important intellectual content, (3) final approval of the version to be submitted.

Jose Tinajero: (1) the conception and design of the study, or acquisition of data, or analysis and interpretation of data, (2) drafting the article or revising it critically for important intellectual content, (3) final approval of the version to be submitted.

Jianying Zhang: (1) the conception and design of the study, or acquisition of data, or analysis and interpretation of data (3) final approval of the version to be submitted.

Anthony Stein^b, Guido Marcucci, Amandeep Salhotra, Vinod Pullarkat, Karamjeet S. Sandhu, Brian J. Ball, Hoda Pourhassan, Paul Koller: (2) drafting the article or revising it critically for important intellectual content, (3) final approval of the version to be submitted.

Data availability

All data generated or analysed during this study are included in this article. Further inquiries can be directed to the corresponding author.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Dat Ngo

Jose Tinajero

References

Marcucci

Haferlach

Dohner

. Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol 2011 Feb 10; 29: 475–486.

Pratz

Levis

. How I treat FLT3-mutated AML. Blood 2017 Feb 2; 129: 565–571.

Frohling

Schlenk

Breitruck

, 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: 4372–4380.

Kottaridis

Gale

Frew

, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom medical research council AML 10 and 12 trials. Blood 2001; 98: 1752–1759.

Center for Drug Evaluation and Research. Midostaurin. U.S. Food and Drug Administration. Silver Springs, Maryland, USA), n.d. Retrieved January 31, 2023, from https://www.fda.gov/drugs/resources-information-approved-drugs/midostaurin.

Stone

Mandrekar

Sanford

, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017 Aug 3; 377: 454–464.

Rydapt (midostaurin) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation, November 2021.

Sechaud

Sinclair

Grosch

, et al. Evaluation of drug-drug interactions between midostaurin and strong CYP3A4 inhibitors in patients with FLT-3-mutated acute myeloid leukemia (AML). Cancer Chemother Pharmacol 2022 Jul; 90: 19–27.

Cornely

Maertens

Winston

, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007 Jan 25; 356: 348–359.

10.

Maertens

Girmenia

Brüggemann

, 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 Dec 1; 73: 3221–3230.

11.

Dohner

Estey

Grimwade

, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017; 129: 424–447.

12.

Stemler

de Jonge

Skoetz

, et al. Antifungal prophylaxis in adult patients with acute myeloid leukaemia treated with novel targeted therapies: a systematic review and expert consensus recommendation from the European hematology association. Lancet Haematol 2022 May; 9: e361–e373.

13.

Stemler

Koehler

Maurer

, et al. Antifungal prophylaxis and novel drugs in acute myeloid leukemia: the midostaurin and posaconazole dilemma. Ann Hematol 2020 Jul; 99: 1429–1440.

14.

Rausch

DiPippo

Jiang

, et al. Comparison of mold active triazoles as primary antifungal prophylaxis in patients with newly diagnosed acute myeloid leukemia in the era of molecularly targeted therapies. Clin Infect Dis 2022 Oct 29; 75: 1503–1510.

15.

Logan

Koura

Taplitz

. Updates in infection risk and management in acute leukemia. Hematology Am Soc Hematol Educ Program 2020 Dec 4; 2020: 135–139.