Observational Study on the Incidence of Infections in Patients With Relapsed/Refractory FMS-like Tyrosine Kinase 3 Acute Myeloid Leukemia Treated With Gilteritinib
Conditions: Acute Myeloid Leukemia
Sponsor: University of Rome Tor Vergata

GilteRInf 2022 vers. 1 of 14 March 2022 
 
Observa(onal study on the incidence of infec(ons in pa(ents with relapsed/refractory FLT3+ 
acute myeloid leukemia treated with Gilteri(nib  
SEIFEM-GilteRInf 2022 (Gilteri(nib Related Infec(ons) Study. 
 
 
Background and study ra(onale 
 
Acute myeloid leukemia (AML) paBents with refractory or relapsed (R/R) disease aEer inducBon 
chemotherapy have a poor prognosis with standard chemotherapy [1]. The prognosis may be further 
aggravated by the suscepBbility to infecBon of this category of paBents oEen due to persistent 
neutropenia [2][3]. 
AcBvaBng mutaBons of FMS-like tyrosine kinase 3 (FLT3) are observed in approximately 30 percent 
of AML cases [4] mainly as in-frame internal tandem duplicaBons (ITDs) within the juxtamembrane 
region of the protein or as missense point mutaBons in the tyrosine kinase domain (TKD).  FLT3 is 
expressed in early hematopoieBc stem and progenitor cells and regulates their proliferaBon and 
diﬀerenBaBon. In paBents with AML, the presence of the FLT3 mutaBon negaBvely aﬀects survival, 
both at diagnosis and upon failure of iniBal therapy [5]. 
Over the years, several FLT3 inhibitors, currently in development or approved for the treatment of 
AML, have been devised and vary in kinase selecBvity, potency, and clinical acBvity. 
GilteriBnib, is a novel selecBve tyrosine kinase inhibitor (TKI) that acts by showing greater speciﬁcity 
for FLT3 and higher potency than the ﬁrst generaBon of TKIs, compeBBvely inhibits the ATP-binding 
site of FLT3 receptors, leading to inhibiBon of receptor signaling and thus cell cycle disrupBon. 
Its approval by the Food and Drug AdministraBon, with indicaBon for FLT3-posiBve R/R LMA (FLT3+), 
is based on the results of the phase 3 ADMIRAL study, which demonstrated its superiority over 
chemotherapy in this seZng [6]. 
In the study, with a median follow-up of 17.8 months, median Overall Survival (OS) was signiﬁcantly 
longer (by 3.7 months) in the GilteriBnib arm than in the salvage chemotherapy arm. 
OS rates at 12, 18 and 24 months in paBents receiving GilteriBnib were 37%, 27% and 20%, 
respecBvely (compared with 19%, 15% and 14% in the comparison arm).  
 
 
 
 
Febrile neutropenia was the most common grade  3 adverse event in the GilteriBnib arm (45.9%), 
with pneumonia and sepBc shock the most common fatal adverse events (1.2% and 0.8% of cases, 
respecBvely) [7]. 
In view of recent approval (FDA 2018, EMA 2019), there is a lack of real-life experience in the 
literature on the management and outcome of infecBous issues, which could be signiﬁcant given the 
frailty of the paBents for whom GilteriBnib is intended. 
We also know that GilteriBnib is mainly metabolized through CYP3A4, so there is a recommendaBon 
in the data sheet to avoid concomitant use of strong CYP3A4 inducers. The phase I/II CHRYSALIS 
study [8], which evaluated potenBal interacBons between GilteriBnib and moderate and strong 
CYP3A4 inhibitors (e.g., some anBfungals such as ﬂuconazole, voriconazole, and posaconazole and 
some anBbioBcs such as clarithromycin, erythromycin, and azithromycin), demonstrated a less than 
2-fold increase in exposure to GilteriBnib with concomitant administraBon of a strong CYP3A4 
inhibitor. However, this increase was not considered 
clinically signiﬁcant because the incidence of AEs did not diﬀer in the two groups.  
In a drug-drug interacBon study, the eﬀects of moderate CYP3A4 inhibitors (e.g., ﬂuconazole) and 
strong CYP3A4 inhibitors (e.g., itraconazole) on the pharmacokineBcs of GilteriBnib were evaluated. 

GilteRInf 2022 vers. 1 of 14 March 2022 
 
The results showed that itraconazole was associated with a signiﬁcant increase in systemic exposure 
of GilteriBnib (~2.3-fold), while ﬂuconazole was associated with a smaller increase (~1.43-fold) [9]. 
However, in the ADMIRAL study, the use of posaconazole, itraconazole, and voriconazole was not 
allowed, and thus the experience of administering these drugs together with GilteriBnib is currently 
limited [10]. 
It can be seen from the data sheet that dose reducBon of GilteriBnib in case of prophylaxis with 
azoles is not recommended, but close monitoring of GilteriBnib-related toxicity is recommended 
[11]. 
At present, experiences analyzing the incidence of invasive fungal infecBons in paBents on 
GilteriBnib (25%) [12], whether prophylacBcally treated or not, are rare. 
In light of this evidence, it also becomes essenBal to evaluate the incidence of side eﬀects related to 
the use of anBbioBc/anBfungal/anBviral drugs in the prophylaxis and treatment of infecBons in the 
seZng of relapsed/refractory paBents undergoing conBnuous therapy such as GilteriBnib. 
 
Study design 
 
The study is observaBonal, retrospecBve-prospecBve, mulBcenter "real-life" study involving 26 
centers belonging to the SEIFEM group. Regarding the retrospecBve part, clinical data will be 
collected on all paBents with LMA FLT3+ (ITD or TKD mutaBon) treated with GilteriBnib from when 
the drug was approved and marketed in Italy (April 2, 2020) unBl April 30, 2022. Enrollment in the 
prospecBve cohort will have an esBmated duraBon of 24 months from the Bme of study approval. 
PaBents enrolled in the last month will be followed for six months from the date of enrollment to 
check for the occurrence of any infecBons. For each case of a paBent receiving salvage monotherapy 
with GilteriBnib, a control paBent with LMA R/R FLT3+ on salvage chemotherapy should also be 
included. 
 
Study Dura(on. 
RelaBve to the prospecBve part, the study will have a total duraBon of 24 months from the ﬁrst 
paBent enrolled and six months of observaBon from the last paBent enrolled. 
 
Popula(on 
 
Inclusion criteria: 
- All paBents with FLT3+ relapsed/refractory AML to any line of therapy treated with GilteriBnib 
- PaBents ≥18 years of age 
- Signature of appropriate informed consent  
Exclusion criteria: 
- PaBents < 18 years old 
 
 
Study Objec(ves. 
The purpose of the present retrospecBve/prospecBve study is to evaluate the "real life" incidence 
of infecBous complicaBons in paBents with relapsed/refractory FLT3+ AML treated with GilteriBnib. 
Primary objec-ve 
To assess "real-life" in paBents with relapsed/refractory FLT3+ LMA treated with GilteriBnib the 
absolute infecBous risk and compare it with relapsed/refractory paBents receiving chemotherapy. 
Secondary objec-ves. 

GilteRInf 2022 vers. 1 of 14 March 2022 
 
- To assess the site, incidence and outcome of bacterial/fungal/viral infecBons in this paBent 
seZng 
- To assess the need for hospitalizaBon and the duraBon of hospitalizaBon 
- To analyze the diﬀerent anBfungal prophylaxis policies in diﬀerent Hematology Centers and 
correlate them with the incidence of infecBon 
- To analyze the incidence of side eﬀects related to the use, in combinaBon with GilteriBnib, of 
anBfungal/anBbacterial/anBviral drugs (in prophylaxis/therapy). 
 
Methods 
The proposed study is retrospecBve-prospecBve, mulBcenter, observaBonal.  
Data will be retrospecBvely collected from all cases observed from April 2, 2020 unBl April 30, 2022 
about the infecBous event and related treatment informaBon (database akached). 
In the prospecBve cohort, enrollment will have an esBmated duraBon of 24 months from the Bme 
of study approval. PaBents enrolled in the last month will be followed for six months thereaEer to 
check for the occurrence of any infecBons. 
Data from paBents with gilteriBnib monotherapy and data from paBents for whom the clinician's 
choice is the use of chemotherapy (consisBng, for example, of the following regimens: FLA-IDA, 
MICE, MEC, intermediate/high-dose cytarabine) will have to be analyzed to assess the infecBous risk 
associated with gilteriBnib monotherapy.  
It is reiterated that since this is an observaBonal study, the choice of therapy is at the discreBon of 
the treaBng hematologist and independent of enrollment in this study. 
Informed consent will be sought from all paBents sBll alive at the Bme of iniBaBon of data collecBon 
and from paBents whose data will be collected prospecBvely. However, it should be noted that since 
this is a study that mainly considers paBents with relapsing hemopathies that could be complicated 
by life-threatening infecBons, the rate of obtainable consents may be reduced due to the mortality 
of these hemopathies. 
The incidence of infecBon will be related to the following variables: 
- Age 
- Sex 
- ComorbidiBes 
- Type of anBmicrobial prophylaxis performed 
- Type of FLT3 mutaBon (ITD vs TKD) 
- Type of response to treatment 
- HospitalizaBon and duraBon 
Any side eﬀects related to the combinaBon of GilteriBnib with anBmicrobial drugs used in 
prophylaxis/therapy by diﬀerent centers will also be evaluated. 
The study will not aﬀect normal care pracBce in any way, as there is no blood sampling for paBents. 
Each paBent and each control will be assigned an idenBﬁcaBon code that will allow the omission of 
any reference that would allow paBent recogniBon. 
Clinical informaBon will pertain to the coordinaBng center and will be collected within a database.  
Based on the following consideraBons: 
- it is assumed that the reference populaBon, or target populaBon from which the sample is drawn 
(78 paBents), is Gaussian distributed with unknown variance; 
- the null hypothesis (superposibility of the two populaBons: sample and target) is rejected if the 
sample mean diﬀers from the mean value of the reference populaBon by an amount, in absolute 
value, equal to or greater than 36.7 percent of the standard deviaBon; 

GilteRInf 2022 vers. 1 of 14 March 2022 
 
- we adopt, for tesBng the hypotheses (null and alternaBve), the two-tailed Gauss z-test with α = 
0.05 (error of the ﬁrst kind) and β = 0.10 (error of the second kind), which implies, as is well known, 
a test power of 90%; 
at least 78 paBents are expected to be enrolled.  
The analysis will be aimed at evaluaBng the distribuBon of infecBous events (viral/bacterial/fungal) 
and idenBfying parameters that signiﬁcantly inﬂuence the outcome of infecBous complicaBon.  
With regard to descripBve staBsBcal analyses, central tendency, variability, symmetry and kurtosis 
will be calculated, all accompanied by appropriate graphical representaBons; with regard to 
inferenBal analyses, in addiBon to mulBvariate binary logisBc regression, parametric and 
nonparametric hypothesis tesBng will be carried out, respecBvely, for quanBtaBve variables with 
parametric tests such as: Student's t-test, Fisher's F-test, etc. and for categorical variables by 
nonparametric tests such as: chi-square, Mann Witney's U, Fisher's exact test, etc. Only results with 
p-values ≤ 0.05 will be considered staBsBcally signiﬁcant.  
 
The study does not involve any expenses related to data collecBon or addiBonal examinaBons.  
Italian Hematology Centers belonging to the SEIFEM Group, which includes both university and 
hospital faciliBes, will parBcipate in the study (Appendix 1: list of parBcipaBng centers).  
Data collecBon and analysis and report preparaBon will be the responsibility of the scienBﬁc board. 
 
DisseminaBon of results 
PublicaBon of results in leading internaBonal scienBﬁc journals dealing with topics related to 
hematology and infecBous diseases. Also, presentaBon of results at major naBonal and internaBonal 
hematology congresses, (American Society of Hematology, European Hematology AssociaBon, 
Italian Society of Hematology)