Regular Article CLINICAL TRIALS AND OBSERVATIONS Follow-up of patients with R/R FLT3-mutation–positive AML treated with gilteritinib in the phase 3 ADMIRAL trial Alexander E. Perl,1 Richard A. Larson,2 Nikolai A. Podoltsev,3 Stephen Strickland,4 Eunice S. Wang,5 Ehab Atallah,6 Gary J. Schiller,7 Giovanni Martinelli,8 Andreas Neubauer,9 Jorge Sierra,10 Pau Montesinos,11 Christian R echer,12 Sung-Soo Yoon,13 Naoko Hosono,14 Downloaded from http://ashpublications.org/blood/article-pdf/139/23/3366/1902710/bloodbld2021011583.pdf by guest on 23 January 2023 Masahiro Onozawa,15 Shigeru Chiba,16 Hee-Je Kim,17 Nahla Hasabou,18 Qiaoyang Lu,18 Ramon Tiu,18 and Mark J. Levis19 1 Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; 2University of Chicago, Chicago, IL; 3Yale School of Medicine, New Haven, CT; 4 Vanderbilt-Ingram Cancer Center, Nashville, TN; 5Roswell Park Comprehensive Cancer Center, Buffalo, NY; 6Division of Hematology and Oncology, Medical College of Wisconsin, Cancer Center-Froedtert Hospital, Milwaukee, WI; 7David Geffen School of Medicine at UCLA, Los Angeles, CA; 8IRCCS Istituto Romag- nolo per lo Studio dei Tumori “Dino Amadori,” IRST S.r.l., Meldola, Italy; 9Universit€ atsklinikum Giessen und Marburg GmbH, Marburg, Germany; 10Hospital de la Santa Creu I Sant Pau and Josep Carreras Leukemia Research Institute, Barcelona, Spain; 11University Hospital La Fe, Valencia, Spain; 12Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer deToulouse Oncopole, Universit e de Toulouse 3 Paul Sabatier, Toulouse, France; 13Seoul National University Hospital, Seoul, Republic of Korea; 14University of Fukui, Fukui, Japan; 15Hokkaido University, Sapporo, Japan; 16Department of Hematology, University of Tsukuba, Tsukuba, Japan; 17Catholic Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 18 Astellas Pharma US, Inc., Northbrook, IL; and 19Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD KEY POINTS The phase 3 ADMIRAL (NCT02421939; Study ID: 2215-CL-0301) trial showed superior  Long-term gilteritinib overall survival in patients with relapsed/refractory FLT3-mutation–positive acute myeloid therapy sustained leukemia (AML) randomized 2:1 to receive the oral FMS-like tyrosine kinase 3 inhibitor remission, leading to gilteritinib vs those randomized to receive salvage chemotherapy (SC). Here we provide a better long-term follow-up of the ADMIRAL trial 2 years after the primary analysis to clarify the long-term survival than chemotherapy in treatment effects and safety of gilteritinib in these patients with AML. At the time of this relapsed/refractory analysis, the median survival follow-up was 37.1 months, with deaths in 203 of 247 and 97 FLT31 AML. of 124 patients in the gilteritinib and SC arms, respectively; 16 gilteritinib-treated patients  The safety profile of remained on treatment. The median overall survival for the gilteritinib and SC arms was gilteritinib was stable 9.3 and 5.6 months, respectively (hazard ratio, 0.665; 95% confidence interval [CI], 0.518, over a 2-year period, 0.853; two-sided P 5 .0013); 2-year estimated survival rates were 20.6% (95% CI, 15.8, with no new or clinically significant safety 26.0) and 14.2% (95% CI, 8.3, 21.6). The gilteritinib-arm 2-year cumulative incidence of signals. relapse after composite complete remission was 75.7%, with few relapses occurring after 18 months. Overall, 49 of 247 patients in the gilteritinib arm and 14 of 124 patients in the SC arm were alive for ≥2 years. Twenty-six gilteritinib-treated patients remained alive for ≥2 years without relapse; 18 of these patients underwent transplantation (hematopoietic stem cell transplantation [HSCT]) and 16 restarted gilteritinib as post-HSCT maintenance therapy. The most common adverse events of interest during years 1 and 2 of gilteritinib therapy were increased liver transaminase levels; adverse event incidence decreased in year 2. Thus, continued and post-HSCT gilteritinib maintenance treatment sustained remission with a stable safety profile. These findings confirm that prolonged gilteritinib therapy is safe and is associated with superior survival vs SC. This trial was registered at www.clinicaltrials.gov as #NCT02421939. Introduction Gilteritinib is a FLT3 inhibitor approved for patients with R/R The emergence of targeted therapies has expanded treatment FLT3-mutation–positive (FLT31) AML based on the phase 3, ran- options for patients with newly diagnosed, relapsed or refractory domized, controlled ADMIRAL trial (NCT02421939; Study ID: (R/R) acute myeloid leukemia (AML).1-5 Compared with chemo- 2215-CL-0301), which reported the superiority of gilteritinib over therapy alone, agents that inhibit FMS-like tyrosine kinase 3 salvage chemotherapy (SC) in this patient population.1 Gilteriti- (FLT3) kinase activity, administered alone or in combination with nib resulted in significantly longer median overall survival (OS; chemotherapy, have improved survival and response rates in 9.3 months) compared with SC (5.6 months; hazard ratio for patients with AML.1,2,4,6,7 death [HR], 0.64; 95% confidence interval [CI], 0.49, 0.83; two- 3366 blood® 9 JUNE 2022 | VOLUME 139, NUMBER 23 sided P , .001). In addition, the combined rates of complete September 20, 2020, 2 years after the primary analysis of the remission and complete remission with partial hematologic ADMIRAL trial. Statistical modeling was not used to determine recovery (CR/CRh) were higher with gilteritinib than with SC, at the timing of this analysis. 34.0% and 15.3%, respectively. Although the survival benefit of gilteritinib was maintained in this trial when data were censored Assessments for transplantation, long-term survival among patients with R/R Response and survival outcomes were assessed in patients AML is generally limited to those who undergo allogeneic who underwent HSCT during the ADMIRAL trial. Treatment hematopoietic stem cell transplantation (HSCT). Even when response was assessed by using modified International accounting for the 2:1 randomization design of the ADMIRAL Working Group criteria, as described in the primary publica- trial, a greater proportion of patients randomized to receive gil- tion.1,8 Complete definitions of treatment response param- teritinib than those assigned to SC underwent allogeneic HSCT eters are presented in supplemental Table 1 (available on during the trial (gilteritinib, n 5 63; SC, n 5 19). Forty-nine of the Blood Web site). The complete composite remission the 63 transplanted gilteritinib-treated patients received post- (CRc) rate was defined as the sum of patients who achieved HSCT maintenance with gilteritinib. After adjustment for expo- CR, CR with incomplete hematologic recovery, and CR with sure duration, gilteritinib was associated with fewer grade $3 incomplete platelet recovery. FLT3 mutation status was Downloaded from http://ashpublications.org/blood/article-pdf/139/23/3366/1902710/bloodbld2021011583.pdf by guest on 23 January 2023 and serious adverse events (AEs) compared with SC. assessed at enrollment (baseline) by a central laboratory using a polymerase chain reaction–based assay (LeukoStrat The primary analysis of the ADMIRAL trial was initiated after a CDx; Invivoscribe Technologies, Inc.) according to pub- prespecified number of survival events to determine an improve- lished methods.9 The median FLT3–internal tandem dupli- ment in median OS (ADMIRAL trial primary end point) with gil- cation (ITD) allelic ratio (defined as the ratio of FLT3-ITD to teritinib; however, a substantial fraction of the study population wild-type FLT3 DNA) was established at 0.77 based on had a short follow-up duration at the time of primary analysis, analyses in 335 evaluable patients; high and low FLT3-ITD thus limiting the evaluation of long-term survival in these allelic ratios were defined as $0.77 and ,0.77, respec- patients. Furthermore, the safety profile associated with the con- tively. Next-generation sequencing was used to detect tinued use of gilteritinib beyond 1 year is not well described. As AML-associated mutations at enrollment, as previously the use of gilteritinib and other FLT3 inhibitors becomes more described by using the ArcherDX myeloid panel.1 prevalent in the treatment of AML, an evaluation of outcomes associated with continued use of FLT3 inhibitors beyond 1 year AEs were assessed and graded by using the Common Ter- and the impact of FLT3 inhibitors as post-HSCT maintenance minology Criteria for Adverse Events (version 4.03). Specific therapy is warranted. AEs of interest included cardiac AEs (eg, arrhythmia, car- diac failure, pericarditis/pericardial effusion); musculoskele- We therefore performed a post hoc analysis of data from the tal AEs (eg, muscle damage or weakness); increased liver ADMIRAL trial, 2 years after the primary analysis, to build on enzyme levels; gastrointestinal (GI) perforation, hemor- results from the primary analysis with respect to the long-term rhage, or obstruction; pericarditis/pericardial effusion; and efficacy of gilteritinib, to characterize patients in the gilteritinib posterior reversible encephalopathy syndrome (PRES). The arm who remained alive for $2 years without relapse, and to incidence of cutaneous squamous cell carcinoma and differ- evaluate the incidence of late-occurring AEs of interest associ- entiation syndrome was also evaluated. ated with continued treatment with gilteritinib beyond 1 year. Statistical analyses Descriptive statistics were used to assess continuous varia- Subjects and methods bles. Categorical data are reported as frequencies and per- Patient population centages. Survival and response outcomes were assessed The ADMIRAL trial enrolled adult patients (aged $ 18 years) in the intention-to-treat population, which included all pa- with confirmed FLT31 AML who were in their first relapse after tients randomly assigned to treatment. Safety outcomes, achieving CR with initial induction therapy or were refractory to including drug exposure, were assessed in the safety analy- initial induction therapy. Patients were randomly assigned 2:1 to sis set, defined as all patients who received $1 dose of the receive gilteritinib 120 mg/d or preselected high- or low- study drug. The Kaplan-Meier method and the Greenwood intensity SC. Further details regarding the patient population formula were used to estimate OS. The HR and CIs were and treatment administration have been described in the pri- used to determine differences in OS between groups. mary publication.1 Because the statistical analysis plan did not include provi- sions for multiplicity correction with respect to evaluation of The study was conducted in accordance with the principles of secondary outcomes or subgroup analyses, these results the Declaration of Helsinki. are reported as point estimates with 95% CIs. Statistical analyses were performed with SAS version 9.3 or higher Data analyses software (SAS Institute, Inc.). The primary analysis of the ADMIRAL trial was triggered by a prespecified number of survival events that were sufficient to power a survival analysis with a power of 90% to detect a 35% Results improvement in median OS at a one-sided a value of 0.0245. At Patient disposition and treatment exposure the time of primary analysis, median follow-up was 17.8 months. As of the September 20, 2020, data cutoff date, there were 203 For this follow-up analysis, we performed a data cut on deaths (82%) in the gilteritinib arm and 97 deaths (78%) in the LONG-TERM GILTERITINIB THERAPY IN R/R FLT3+ AML blood® 9 JUNE 2022 | VOLUME 139, NUMBER 23 3367 SC arm; 16 patients in the gilteritinib arm remained on treat- decreases or dose interruptions increased with exposure ment (Figure 1A). A total of 49 patients in the gilteritinib arm duration. had been alive for $2 years. Overall, 26 of the 49 patients in the gilteritinib arm were living, without relapse, for $2 years; 16 OS, duration of remission, and cumulative of these patients remained on gilteritinib therapy (Figure 1B). relapse rates The most common reasons for discontinuation of gilteritinib At the time of data cutoff, the median time to follow-up for OS were lack of efficacy/AML progression/relapse (54%; n 5 134 of 246), death (13%; n 5 38 of 246, primarily due to AEs [11%; was 37.1 months. The median OS in the gilteritinib and SC arms n 5 27 of 246] or disease progression [3%; n 5 7 of 246]), and remained unchanged at 9.3 and 5.6 months, respectively (HR, AEs (13%; n 5 31 of 246). Subsequent treatment with tyrosine 0.665; 95% CI, 0.518, 0.853; two-sided P 5 .0013) (Figure 2), kinase inhibitors, either alone or in combination with chemother- which was expected based on the number of survival events apy, was administered in 11 patients who were still in remission recorded at the time of the primary analysis. Estimated survival after achieving CRc (gilteritinib, n 5 4; SC, n 5 7). Patients in at 1, 2, and 3 years was longer for each time point in the gilteri- the gilteritinib arm subsequently received commercially available tinib arm. With longer follow-up, the survival benefit of gilteriti- gilteritinib (n 5 3) or quizartinib (n 5 1). Patients in the SC arm nib was maintained in the FLT3-ITD mutation subgroup (HR, Downloaded from http://ashpublications.org/blood/article-pdf/139/23/3366/1902710/bloodbld2021011583.pdf by guest on 23 January 2023 subsequently received sorafenib only (n 5 2), sorafenib and gil- 0.662; 95% CI, 0.511, 0.858) (supplemental Figure 1A) and in teritinib (n 5 1), sorafenib with decitabine (n 5 1), quizartinib patients with a high FLT3-ITD allelic ratio (HR, 0.519; 95% CI, (n 5 1), midostaurin with azacitidine (n 5 1), or another 0.363, 0.742) (supplemental Figure 1C). A survival benefit was unknown/investigational FLT3 inhibitor (n 5 1). At the time of not observed in the FLT3-TKD subgroup (HR, 0.684; 95% CI, data cutoff, 64 patients in the gilteritinib arm and 19 patients in 0.301, 1.552) (supplemental Figure 1B) or in patients with a low the SC arm had undergone HSCT; in both arms, most patients FLT3-ITD allelic ratio (HR, 0.821; 95% CI, 0.563, 1.197) (supple- who underwent transplantation had been preselected for high- mental Figure 1D). The survival benefit of gilteritinib was also intensity chemotherapy (Figure 1C). A total of 40 patients had maintained in patients preselected for high-intensity chemother- resumed gilteritinib treatment post-HSCT. apy (HR, 0.697; 95% CI, 0.507, 0.958) (supplemental Figure 1E) or low-intensity chemotherapy (HR, 0.584; 95% CI, 0.399, 0.857) Among patients in the safety analysis set who had received (supplemental Figure 1F). However, given the small numbers of at least one dose of gilteritinib, 19.5% (n 5 48 of 246) had patients in these subgroups, these findings do not imply defini- $12 months of gilteritinib exposure (supplemental Table 2), tive treatment differences. In the gilteritinib arm, the median and 10.2% (n 5 25 of 246) had $24 months of gilteritinib duration of CR was 23.0 months (interquartile range [IQR], 4.9 exposure. Median relative dose intensity ranged from 98% months-not evaluable); median durations of CRc and CR/CRh in to 100% at exposure durations of ,6 months to $12 the gilteritinib arm were 4.6 months (IQR, 1.9-24.0 months) and months. The proportions of patients who required dose 10.0 months (IQR, 2.8 months-not evaluable), respectively. A ITT population N=371 Gilteritinib SC n=247 n=124 Received Received gilteritinib SC n=246 n=109 Alive Alive n=43 n=12 Remain on gilteritinib n=16 Figure 1. Patient disposition. (A) Disposition according to treatment received. (B) Disposition according to transplantation status: patients remaining alive for $2 years without relapse in the gilteritinib arm. (C) Disposition by preselected chemotherapy: patients remaining alive for $2 years without relapse in the gilteritinib arm. Due to limited follow-up of patients in the SC arm, data related to posttransplant relapse and survival were not available. ITT, intention-to-treat. 3368 blood® 9 JUNE 2022 | VOLUME 139, NUMBER 23 PERL et al B ITT population N=371 Gilteritinib SC n=247 n=124 Received Received gilteritinib SC n=246 n=109 Downloaded from http://ashpublications.org/blood/article-pdf/139/23/3366/1902710/bloodbld2021011583.pdf by guest on 23 January 2023 HSCT No HSCT HSCT No HSCT n=64 n=182 n=19 n=90 Resumed Did not resume Alive t2 years gilteritinib gilteritinib without relapse n=40 n=24 n=8 Alive t2 years Alive t2 years without relapse without relapse n=16 n=2 C ITT population N=371 Gilteritinib SC n=247 n=124 Preselected for Preselected for Preselected for Preselected for high-intensity low-intensity high-intensity low-intensity chemotherapy chemotherapy chemotherapy chemotherapy n=149 n=98 n=75 n=49 HSCT HSCT HSCT HSCT n=55 n=9 n=17 n=2 Alive t2 years Alive t2 years without relapse without relapse n=15 n=3 Figure 1. (continued) The 2-year cumulative relapse rates in gilteritinib-treated patients cumulative incidence of relapse after a best response of CR who achieved a best response of CR or CRc were 52.6% and and after a best response of CRc in patients treated with 75.7%, respectively. For all postbaseline assessments, the gilteritinib is shown (Figure 3A-B). The majority of relapses LONG-TERM GILTERITINIB THERAPY IN R/R FLT3+ AML blood® 9 JUNE 2022 | VOLUME 139, NUMBER 23 3369 1.0 Median OS Gilteritinib 9.3 months SC 5.6 months 0.8 HR (95% CI) = 0.665 (0.518, 0.853); two-sided P=0.0013 Censored Survival probability OS rates (95% CI) Gilteritinib SC 0.6 1 year 36.6% (30.6, 42.7) 19.2% (12.4, 27.2) 2 year 20.6% (15.8, 26.0) 14.2% (8.3, 21.6) 0.4 3 year 15.8% (11.4, 20.7) 10.4% (5.3, 17.6) 0.2 Downloaded from http://ashpublications.org/blood/article-pdf/139/23/3366/1902710/bloodbld2021011583.pdf by guest on 23 January 2023 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 Patients at risk (n) Time (months) Gilteritinib 247 206 158 121 87 73 63 52 49 41 38 34 22 18 10 6 4 2 1 0 SC 124 84 52 34 20 18 15 14 14 11 10 7 7 1 1 0 0 0 0 0 Figure 2. OS in patients with R/R FLT31 AML (intention-to-treat population). after CRc in the gilteritinib arm occurred within 12 months treatment beyond 1 year of treatment initiation (supplemental of enrollment, and relapses rarely occurred after 18 months Table 3). Reasons for discontinuation of gilteritinib within 1 year from enrollment (Figure 3B). We also evaluated the cumula- were treatment-emergent AEs (n 5 4; elevated alanine amino- tive incidence of relapse in the gilteritinib arm from the transferase [ALT]/aspartate aminotransferase [AST] and blood time of randomization and saw no marked change in alkaline phosphatase [n 5 1]; pneumonia [n 5 1], increased relapse incidence (supplemental Figure 2). A meaningful blood bilirubin [n 5 1], and decreased platelet count [n 5 1]), assessment of cumulative relapse rates in the SC arm could physician decision (n 5 1), achievement of CRc after HSCT not be performed because bone marrow samples were only (n 5 1), and progressive disease (n 5 1). Six of the 7 patients collected up to the end of treatment, and nearly all patients who stopped gilteritinib within 1 year underwent HSCT, and 4 in the SC arm had discontinued treatment after #2 treat- of these 6 patients resumed gilteritinib post-HSCT. Of the 19 ment cycles. patients who continued gilteritinib treatment beyond 1 year, 12 underwent HSCT, and all 12 resumed gilteritinib therapy post- Outcomes in gilteritinib arm patients who were HSCT. All 19 patients who continued gilteritinib therapy beyond alive for ≥2 years without relapse 1 year achieved CR, and 2 of 7 patients who stopped gilteritinib The median duration of follow-up was 39.5 months for the 26 therapy within 1 year achieved CR. gilteritinib-treated patients who were alive for $2 years without relapse. Baseline characteristics of these 26 patients are presented Post-HSCT gilteritinib maintenance therapy in supplemental Table 3. Eighteen of these patients underwent Overall, 40 (62.5%) of the 64 gilteritinib-treated patients who HSCT during the trial, and 16 resumed gilteritinib post-HSCT. underwent transplantation during the study received post-HSCT Regardless of gilteritinib treatment duration, most patients who maintenance therapy with gilteritinib (median duration of expo- remained alive without relapse for $2 years were aged ,65 years sure, 9.70 months; IQR, 1.69-28.3 months). Median time to initi- (84.6%; n 5 22 of 26), preselected for high-intensity chemother- ation of post-HSCT gilteritinib maintenance therapy from the apy before randomization (76.9%; n 5 20 of 26), and had not time of HSCT was 55 days (range, 32-91 days). Seven of the 40 received prior treatment with midostaurin or sorafenib (96.1%; n patients who resumed gilteritinib after HSCT had dose 5 25 of 26). An equal number of patients had high or low base- decreases due to AEs (thrombocytopenia, pleural effusion, line FLT3-ITD allelic ratios (46.2%; both n 5 12); 12 patients (46.2%) had baseline NPM1 mutations. All 8 gilteritinib-treated peripheral edema, weight gain, increased blood creatine phos- patients who did not undergo HSCT had relapsed disease at phokinase, pleural thickening, increased ALT, decreased neutro- baseline, and almost all of these 8 patients (87.5%; n 5 7 of 8) phil count, and hypokalemia). One of these patients had a dose were aged ,65 years and had undergone HSCT before study increase from 120-mg to 200-mg gilteritinib prior to HSCT entry (supplemental Table 4). Most of these patients had also before the dose decrease back to 120 mg immediately after been preselected for high-intensity chemotherapy (62.5%; n 5 5 HSCT due to the development of pleural effusion. Among of 8), had a low FLT3-ITD allelic ratio at baseline (62.5%; n 5 5 of patients in the gilteritinib arm who received post-HSCT gilteriti- 8), and had NPM1 comutations (62.5%; n 5 5 of 8). nib maintenance therapy, cumulative 24-month relapse rates were 0% in patients whose response before HSCT was CR Seven of the 26 patients had stopped gilteritinib therapy within (n 5 4) or CR/CRh (n 5 9) and 18.6% for patients who had a 1 year of treatment initiation, and 19 had continued gilteritinib pretransplant response of CRc (n 5 20). 3370 blood® 9 JUNE 2022 | VOLUME 139, NUMBER 23 PERL et al A 1.0 Gilteritinib Censored 0.8 Cumulative rate of relapse 0.6 0.4 0.2 Downloaded from http://ashpublications.org/blood/article-pdf/139/23/3366/1902710/bloodbld2021011583.pdf by guest on 23 January 2023 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 Patients at risk (n) Time (months) Gilteritinib 57 43 35 30 26 23 20 16 14 12 10 8 6 4 3 1 0 0 0 0 B 1.0 0.8 Cumulative rate of relapse 0.6 0.4 0.2 Gilteritinib Censored 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 Patients at risk (n) Time (months) Gilteritinib 134 72 43 37 29 24 21 19 18 15 13 12 6 4 4 2 1 1 1 0 Figure 3. Cumulative incidence of relapse in patients with R/R FLT31 AML in the gilteritinib arm. (A) Cumulative incidence of relapse after CR. (B) Cumulative inci- dence of relapse after CRc. Other AML therapies in gilteritinib arm patients HSCT. Overall, 80.7% (n 5 21 of 26) of transplant patients who underwent HSCT in the gilteritinib arm relapsed before receiving other AML Overall, 26 patients in the gilteritinib arm who underwent therapy; the median time from HSCT to initiation of other on-study HSCT received other AML therapies. Of the 64 AML therapy in these patients was 3.5 months. gilteritinib-treated patients who underwent on-study HSCT, 24 did not resume gilteritinib after HSCT; 15 of these 24 Other AML therapies (excluding HSCT) administered in trans- patients received subsequent therapy with other agents, plant patients included high-intensity chemotherapy (46.2%; and 9 received HSCT as subsequent therapy. Among the 40 n 5 12 of 26), low-intensity chemotherapy (34.6%; n 5 9 of 26), patients who resumed gilteritinib after on-study HSCT, 12 and tyrosine kinase inhibitors (34.6%; n 5 9 of 26 [sorafenib, received other AML drug therapies after discontinuing gil- 26.9%, n 5 7* of 26; or midostaurin, 11.5%, n 5 3* of 26; teritinib. Of the 15 patients who did not resume gilteritinib *includes one patient who received both sorafenib and midos- after on-study HSCT, 5 received other AML therapy after taurin]). For the 24 patients who did not resume gilteritinib after LONG-TERM GILTERITINIB THERAPY IN R/R FLT3+ AML blood® 9 JUNE 2022 | VOLUME 139, NUMBER 23 3371 Within 12 months of gilteritinib (n=246) After 12 months of gilteritinib (n=50) Increased ALT Increased AST Myalgia Blood creatine phosphokinase increased Blood bilirubin increased Muscular weakness Downloaded from http://ashpublications.org/blood/article-pdf/139/23/3366/1902710/bloodbld2021011583.pdf by guest on 23 January 2023 Prolonged QT interval Grade 1–2 Grade ≥3 Syncope Hypoxia Pulmonary edema Pericardial effusion Gamma-glutamyl transferase increased Hyperbilirubinemia Transaminase increased 50 40 30 20 10 0 10 20 30 40 50 Patients (%) Figure 4. AEs of interest during and after the first year of gilteritinib therapy in patients with R/R FLT31 AML. HSCT, other AML drug therapies were administered in 10 Five patients experienced myalgia and 2 experienced prolonged patients after a relapse. Five of these patients received subse- QT intervals during both years 1 and 2 of gilteritinib therapy. quent treatment with tyrosine kinase inhibitors: sorafenib alone (n 5 1), sorafenib plus chemotherapy (n 5 1), midostaurin plus AEs of interest leading to gilteritinib dose reductions occurred in chemotherapy (n 5 1), midostaurin plus chemotherapy followed 5.7% (n 5 14 of 246) of patients; dose reductions occurred due by sorafenib plus chemotherapy (n 5 1), and gilteritinib (n 5 1). to increased ALT level (n 5 5), prolonged QT interval (n 5 3), increased blood creatine phosphokinase level (n 5 2), increased AEs of interest in patients treated with AST level (n 5 1), increased blood bilirubin level (n 5 1), syn- gilteritinib cope (n 5 1), muscular weakness (n 5 1), and cardiac failure The most common AEs of interest were increased levels of ALT (n 5 1). Serious AEs of interest occurred in 20.3% (n 5 50 of and AST (Figure 4; supplemental Figure 3), which were the most 246) of patients treated with gilteritinib; the most common were frequent AEs of interest associated with gilteritinib during the increased ALT level (n 5 13), increased AST level (n 5 10), syn- first and second year of treatment. Most instances of increased cope (n 5 7), cardiac arrest (n 5 4), cardiac failure (n 5 3), myo- ALT and AST levels were grade 1/2 in severity. Compared with sitis (n 5 3), pericarditis (n 5 3), and pericardial effusion (n 5 3). the first year of gilteritinib therapy, the second year saw a Overall, 5.3% (n 5 13 of 246) of patients discontinued gilteritinib decline in the incidence of these and other AEs of interest. because of AEs of interest. Specific AEs of interest leading to treatment discontinuation in .1 patient included increased ALT Fourteen (5.7%) of 246 gilteritinib-treated patients experienced level (n 5 5), increased AST level (n 5 4), and cardiac arrest an AE of interest occurring in the first year of gilteritinib therapy (n 5 2). Increased blood bilirubin, increased blood creatine that persisted into the second year of treatment. Twelve patients phosphokinase, duodenal perforation, large intestinal perfora- experienced increased ALT/AST levels during both the first and tion, pericardial effusion, and pericarditis each led to discontinu- second year of gilteritinib treatment; persistently increased levels ation in individual patients. Overall, 37 gilteritinib-treated of blood creatine phosphokinase (n 5 4), blood bilirubin (n 5 3), patients developed graft-versus-host disease (GVHD); 15 of and gamma-glutamyl transferase (n 5 2) were also observed. these patients developed GVHD after resuming gilteritinib 3372 blood® 9 JUNE 2022 | VOLUME 139, NUMBER 23 PERL et al therapy. A total of 11 patients developed grade $3 GVHD, provides the first evidence that an FLT3 inhibitor administered including 1 fatal case of intestinal acute GVHD. in the salvage setting can afford an ongoing and absolute sur- vival benefit over SC in patients with R/R FLT31 AML. Differentiation syndrome, PRES, and cutaneous squamous cell carcinoma were reported in 1 patient each in the gilteritinib arm. We previously reported that survival in ADMIRAL was superior Differentiation syndrome and PRES occurred during the first year with gilteritinib compared with SC, even after censoring for of treatment, and cutaneous squamous cell carcinoma occurred transplantation. With a longer follow-up, most (62%) gilteritinib during the second year of treatment. Cardiac AEs of interest that arm patients remaining in initial remission after at least 2 years occurred during the first year of treatment with gilteritinib from randomization underwent HSCT while in CRc followed by included pericardial effusion (n 5 10), pericarditis (n 5 5), cardiac gilteritinib maintenance. A detailed analysis of the role of HSCT, arrest (n 5 4), cardiac failure (n 5 4), congestive cardiac failure (n pretransplant response, and posttransplant maintenance with 5 2), ventricular tachycardia (n 5 2), and ventricular arrhythmia (n gilteritinib as a predictor of survival is beyond the scope of the 5 1); all 4 cases of cardiac arrest, 2 cases of pericardial effusion, current article. The small sample size and lack of randomization and 1 case of congestive cardiac failure were fatal. All cases of car- preclude any definitive statements regarding the utility of post- diac arrest were unrelated to gilteritinib therapy. During the sec- transplant gilteritinib or comparisons with no posttransplant Downloaded from http://ashpublications.org/blood/article-pdf/139/23/3366/1902710/bloodbld2021011583.pdf by guest on 23 January 2023 ond year of gilteritinib therapy, cardiac AEs of interest included maintenance therapy. cardiorespiratory arrest and ventricular tachycardia (both, n 5 1) and pericardial effusion (n 5 1); none of these AEs was fatal. GI Administration of FLT3-targeted therapy in the posttransplant AEs of interest, namely GI perforation, hemorrhage, or obstruction AML setting has been evaluated in studies of quizartinib10,11 or during the first year of gilteritinib therapy, included GI hemor- sorafenib.6,7,12,13 A consistent finding among these trials is pro- rhage (n 5 3), lower GI hemorrhage (n 5 2), intestinal perforation longed protection from relapse and improvement in progres- (n 5 2), and rectal hemorrhage (n 5 1); 2 cases of intestinal perfo- sion/disease-free survival or OS among patients who received ration were fatal. A case of impaired gastric emptying and a case these agents in the posttransplant setting.6,7,10-12 However, of fatal duodenal perforation occurred during the second year of most patients in trials of posttransplant sorafenib were in first gilteritinib therapy. AEs of interest related to liver dysfunction dur- CR6,7,12 and therefore had a relatively lower relapse risk com- ing the first year of gilteritinib therapy included hyperbilirubinemia pared with the R/R AML population. Thus, caution is warranted (n 5 9; grade 3, n 5 4), abnormal liver function (n 5 5), and hepa- when extrapolating findings from trials of posttransplant sorafe- tomegaly (n 5 2). During the second year of gilteritinib therapy, 2 nib therapy after first CR to those from studies of posttransplant cases of abnormal liver function (grade 3, n 5 1) and 1 case of FLT3 inhibitor therapy in R/R AML. In the current study, 2-year hepatosplenomegaly were observed. cumulative relapse rates were low in patients achieving CR before allogeneic HSCT. The benefit of post-HSCT gilteritinib During the first year of treatment with gilteritinib, 14.2% (n 5 35 maintenance in first remission is currently being assessed in an of 246) of patients experienced AEs of interest leading to dose ongoing prospective randomized trial (#NCT02997202). How- reduction, with increased ALT (n 5 5), neutropenia (n 5 4), ever, for the aforementioned reasons, the risk–benefit ratio of thrombocytopenia (n 5 3), prolonged QT interval (n 5 3), gilteritinib maintenance therapy could be different in the con- decreased neutrophil count (n 5 3), and drug eruption (n 5 2) text of first remission vs remission in the R/R AML setting, and being the most common. During the second year of treatment, the optimal duration of gilteritinib maintenance therapy may 8% (n 5 4 of 50) of patients experienced AEs of interest leading differ in these 2 scenarios. to dose reduction; these included peripheral edema, increased blood creatine phosphokinase, increased weight, hypokalemia, The most common AEs of interest associated with gilteritinib and pleural effusion (all, n 5 1). were increased liver enzyme (ALT or AST) levels. Only one patient experienced differentiation syndrome, PRES, or sec- ondary cutaneous malignancy. Because symptoms of differen- Discussion tiation syndrome can be nonspecific and might have been This follow-up of the ADMIRAL trial confirms the survival benefit captured by other AEs (eg, fever, pulmonary infiltrate or pneu- associated with gilteritinib previously reported at the time of pri- monia, peripheral edema, pleural effusion, and pericardial mary analysis and shows that 11% of patients in the gilteritinib effusion), close monitoring for differentiation syndrome is war- arm survived for at least 2 years in an ongoing remission. Most ranted during gilteritinib therapy, including considerations for frequently, these patients were aged ,65 years and underwent corticosteroid use. No new significant safety signals related to HSCT after initial gilteritinib therapy that led to CRc, followed by gilteritinib therapy emerged during the second year of treat- post-HSCT gilteritinib maintenance therapy. However, a smaller ment; however, a small risk remains for late-occurring cardiac number who discontinued gilteritinib also remained in remission events, liver dysfunction, and GI events. Compared with the at 2 years. Estimated OS rates at 1, 2, and 3 years were higher first year of gilteritinib therapy, the overall incidence of AEs in the gilteritinib arm than in the SC arm, although the small declined during the second year of treatment. Although many number of patients alive at 2 or 3 years limits validity of cross- long-term gilteritinib-treated patients also received HSCT, an arm comparisons. Although the primary analysis of the ADMI- interaction between hepatic or GI AEs and HSCT with or with- RAL trial reported superior OS with gilteritinib, relatively few out subsequent GVHD was not evaluated. AEs of interest patients had long-term follow-up, and the long-term survival tra- occurred more frequently with gilteritinib compared with SC, jectories for the gilteritinib and SC arms were likely to overlap but this does not necessarily suggest that gilteritinib was more with time. With a median follow-up of .3 years, our analysis toxic than SC, as the short duration of SC (1-2 cycles) con- suggests that gilteritinib may be associated with superior survival founds direct comparison during follow-up. Prior analysis from compared with SC for years after randomization. This finding ADMIRAL showed that, when corrected for therapy duration, LONG-TERM GILTERITINIB THERAPY IN R/R FLT3+ AML blood® 9 JUNE 2022 | VOLUME 139, NUMBER 23 3373 gilteritinib was associated with fewer toxicities overall and less Bristol Myers Squibb, CTI BioPharma, PharmaEssentia, Constellation frequent severe and treatment-related AEs than SC.1 Pharmaceuticals, Cogent Biosciences, and AbbVie; and research fund- ing granted to his institution from Pfizer, Celgene, CTI BioPharma, Boehringer Ingelheim, Astellas Pharma, Daiichi Sankyo, Sunesis Pharma- The strength of any post hoc analysis is limited and may be sub- ceuticals, Jazz Pharmaceuticals, Astex Pharmaceuticals, Genentech, AI ject to reporting bias. Analysis of survival across the treatment Therapeutics, Samus Therapeutics, Arog Therapeutics, and Kartos Ther- arms at defined time points was neither prespecified nor was apeutics. S.S. reports consulting or advisory fees from AbbVie, Astellas the study powered to address this question. Other limitations of Pharma, Jazz Pharmaceuticals, Kite, a Gilead company, Novartis, and this analysis include the small number of patients evaluated for Pfizer; and research funding at an institutional level from AbbVie, Astel- las Pharma, Inc., Celator/Jazz, Celgene, Daiichi Sankyo, Karyopharm pretransplant and posttransplant outcomes and the lack of a Therapeutics, Menarini, Novartis, and Sunesis Pharmaceuticals. E.S.W. second randomization and/or placebo group to quantify the reports consulting fees from MacroGenics, PTC Therapeutics, Genen- benefits of posttransplant maintenance for either arm. There tech, AbbVie, Jazz Pharmaceuticals, and BMS; and speakers bureau also could be imbalances with respect to transplant-preparative from Pfizer and Stemline. G.J.S. reports stock holdings for BMS, Pfizer, regimens, donors, and other factors that contribute to post- and J&J; research funding from Agios, Amgen, Incyte, Novartis, Cel- gene, AbbVie, Actinium, Ariad, Celator, Constellation, Cyclacel, Daiichi transplant survival, for which we did not control. Because adjust- Sankyo, Deciphera, DeltaFly, BMS, Forma, Fujifilm, Gamida, ments for multiple comparisons for subgroup analyses were not Genentech-Roche, Geron, Jazz Pharmaceuticals, Karyopharm, Kite Downloaded from http://ashpublications.org/blood/article-pdf/139/23/3366/1902710/bloodbld2021011583.pdf by guest on 23 January 2023 made, the results herein should not be inferred as definitive pharma, Mateon, Onconova, Pfizer, Regimmune, Samus, Sangamo, Tol- treatment effects. A major reason for missing data are that the ero, and Trovagene; research grants from Astellas Pharma, Agios, vast majority of patients in the SC arm discontinued within the Amgen, Incyte, Novartis, Celgene, AbbVie, Actinium, Ariad, Celator, Constellation, Cyclacel, Daiichi Sankyo, Deciphera, DeltaFly, BMS, first 2 treatment cycles, resulting in an insufficient number of Forma, Fujifilm, Gamida, Genentech-Roche, Geron, Jazz Pharmaceuti- bone marrow samples for assessment of remission status cals, Karyopharm, Kite Pharma, Mateon, Onconova, Pfizer, Regimmune, beyond cycle 2. As such, follow-up data related to the inci- Samus, Sangamo, Tolero, and Trovagene; speakers bureau from Incyte, dence of relapse, posttransplant outcomes, and maintenance Celgene, Sanofi, Gilead, and Stemline; and consultancy from Novartis, therapy were not available for a considerable number of AstraZeneca, Amgen, Ono Pharma, and Kaiser Permanente. G.M. SC-treated patients. Finally, FLT3 mutation clearance before or reports grant funding and consultancy fees from Amgen, Ariad, Incyte, Pfizer, Roche, Celgene, Janssen, AbbVie, and Novartis. J.S. reports per- after HSCT was not systematically evaluated, which, based on sonal fees from Astellas, Jazz Pharmaceuticals, AbbVie, Daiichi Sankyo, data from earlier studies of gilteritinib,14,15 likely had an impact and Pfizer; and grants and personal fees from Novartis, outside the sub- on response and survival profiles. mitted work. P.M. reports research support from Pfizer, AbbVie, and Daiichi Sankyo; consultancy from Celgene, Pfizer, and AbbVie; and In conclusion, patients with R/R FLT31 AML in the ADMIRAL trial speakers bureau from Astellas, Novartis, and Janssen. C.R. reports research grants from AbbVie, Amgen, Novartis, Celgene, Jazz Pharma- continue to benefit from long-term therapy with gilteritinib years ceuticals, Agios, Chugai, MaatPharma, Astellas, Roche, and Daiichi San- after randomization, and an ongoing survival benefit may be kyo; and an advisory role for AbbVie, Sunesis, Janssen, Jazz afforded by gilteritinib therapy. Both continued gilteritinib treat- Pharmaceuticals, Novartis, Celgene, Otsuka, Astellas, Daiichi Sankyo, ment and post-HSCT maintenance therapy with gilteritinib MacroGenics, Roche, and Pfizer. S.-S.Y. reports consulting from Jans- seemed to sustain remission achieved with this drug or with sen, Takeda, Amgen, and Celgene/Jazz; honoraria from Novartis; and research funding from Kyowa Kirin, Roche/Genentech, and Yuhan. S.C. HSCT. The safety profile of gilteritinib seems stable at 2 years, reports subsidy from Astellas, Ono Pharmaceutical Co., Kyowa-Kirin, with no new clinically significant safety signals. Takeda, Sanofi, Chugai Pharmaceutical Co., and BMS. H.-J.K. reports honoraria from AbbVie; honoraria and consultancy from Amgen, AML Hub, Astellas, Celgene, Daiichi Sankyo, Novartis, SL VaxiGen, Yuhan, Acknowledgments Janssen; and grants from BL&H, outside the submitted work. Q.L., N. Medical writing/editorial support was provided by Kalpana Vijayan, Hasabou, and R.T. are employees of Astellas. M.J.L. reports grants and Cheryl Casterline, and Elizabeth Hermans, of Peloton Advantage, personal fees from Astellas and Fujifilm; and personal fees from Daiichi LLC, an OPEN Health company, and funded by the study sponsor. Sankyo, Amgen, and Menarini. The remaining authors declare no com- peting financial interests. This study was funded by Astellas Pharma, Inc. ORCID profiles: A.E.P., 0000-0002-1463-2231; R.A.L., 0000-0001-9168- 3203; N.A.P., 0000-0002-3657-778X; A.N., 0000-0002-7606-8760; P.M., Authorship 0000-0002-3275-5593; C.R., 0000-0002-3332-4525; S.-S.Y., 0000-0003- Contribution: A.E.P., N. Hasabou, and M.J.L. contributed to the study 2591-7459; S.C., 0000-0001-7803-7338; H-J.K., 0000-0003-4098-3366; design; and all authors contributed to the acquisition, analysis, and inter- M.J.L., 0000-0003-0473-6982. pretation of study data; critically reviewed the manuscript; and provided * final approval. Correspondence: Alexander E. Perl, 12-154 South Tower, Perelman Center for Advanced Medicine, Division of Hematology/Oncology, Per- Conflict-of-interest disclosure: A.E.P. reports grants, personal fees, and elman School of Medicine at the University of Pennsylvania, 3400 Civic nonfinancial support from Astellas, during the conduct of the study; Center Blvd, Philadelphia, PA 19104; e-mail: alexander.perl@ grants, personal fees, and nonfinancial support from Daiichi Sankyo; pennmedicine.upenn.edu. grants and personal fees from AbbVie and Actinium Pharmaceuticals; personal fees from Agios, Loxo, LLS/Beat AML, and Forma; nonfinancial support from Arog; personal fees and nonfinancial support from New Footnotes Link Genetics, Novartis, Takeda, and Jazz; and grants from Bayer and Biomed Valley Discoveries, outside the submitted work. R.A.L. reports Submitted 6 April 2021; accepted 16 December 2021; prepublished consulting from Amgen, Novartis, Celgene, ARIAD, CVS Caremark, online on Blood First Edition 26 January 2022. DOI 10.1182/ Astellas Pharma, DAVA Pharmaceuticals, and Epizyme; patents from blood.2021011583. UpToDate, Inc.; and research funding from Daiichi Sankyo, Celgene, Astellas Pharma, Novartis, Rafael Pharmaceuticals, Cellectis, and Forty Researchers may request access to anonymized participant-level data, trial- Seven. N.A.P. reports consulting and advisory fees from Alexion, Pfizer, level data, and protocols from Astellas-sponsored clinical trials at www. Celgene, Agios Pharmaceuticals, Blueprint Medicines, Incyte, Novartis, clinicalstudydatarequest.com. The Astellas criteria on data sharing may be 3374 blood® 9 JUNE 2022 | VOLUME 139, NUMBER 23 PERL et al accessed at https://clinicalstudydatarequest.com/Study-Sponsors/Study- The publication costs of this article were defrayed in part by page Sponsors-Astellas.aspx. charge payment. 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Xuan L, Wang Y, Huang F, et al. Sorafenib of a phase 1 study of quizartinib as under Creative Commons Attribution-NonCommercial- maintenance in patients with FLT3-ITD acute maintenance therapy in subjects with acute NoDerivatives 4.0 International (CC BY-NC-ND 4.0), myeloid leukaemia undergoing allogeneic myeloid leukemia in remission following permitting only noncommercial, nonderivative use with haematopoietic stem-cell transplantation: an allogeneic hematopoietic stem cell attribution. All other rights reserved. LONG-TERM GILTERITINIB THERAPY IN R/R FLT3+ AML blood® 9 JUNE 2022 | VOLUME 139, NUMBER 23 3375