Outcomes in Patients with FLT3-Mutated Relapsed/ Refractory Acute Myelogenous Leukemia Who Underwent Transplantation in the Phase 3 ADMIRAL Trial of Gilteritinib versus Salvage Chemotherapy

Perl, Alexander E.; Larson, Richard A.; Podoltsev, Nikolai A.; Strickland, Stephen A.; Wang, Eunice S.; Atallah, Ehab; Schiller, Gary J.; Martinelli, Giovanni; Neubauer, Andreas; Sierra, Jordi; Montesinos, Pau; Récher, Christian; Yoon, Sung‐Soo; Maeda, Yoshinobu; Hosono, Naoko; Onozawa, Masahiro; Kato, Takuya; Kim, Hee‐Je; Hasabou, Nahla; Nuthethi, Rishita; Tiu, Ramon V.; Levis, Mark J.

doi:10.1016/j.jtct.2022.12.006

Cited by 21 publications

(5 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In patients who underwent BM transplantation and resumed gilteritinib, the most frequent AEs included diarrhea (40%) and one case of fatal acute GI graft-versus-host disease (GVHD) [29].…”

Section: Discussionmentioning

confidence: 99%

Severe Gastrointestinal Toxicity Following the Use of Gilteritinib: A Case Series and Analysis of Postmarketing Surveillance Data

Gozzo,

Nardo,

Brancati

et al. 2023

Healthcare

View full text Add to dashboard Cite

Gilteritinib has been approved as monotherapy in adults with acute myeloid leukemia (AML) FLT3 mutated with relapsed or refractory disease, in light of its advantages in terms of survival and the favorable safety profile. Hepatobiliary disorders and musculoskeletal and connective tissue disorders represent the most frequent adverse reactions associated with gilteritinib, whereas the most frequent serious adverse reaction is acute kidney injury. In the summary of product characteristics, gastrointestinal (GI) events are indicated as very common, in particular diarrhea, nausea and stypsis. Furthermore, serious GI disorders have been observed with gilteritinib in clinical trials, including GI hemorrhage, GI perforation and GI obstruction. However, the association with the FLT3 inhibitor has not been confirmed. Nevertheless, serious GI AEs have been recognized as an important potential risk to be monitored in postmarketing surveillance. We present three cases of serious self-limiting GI events observed in patients on gilteritinib treatment for AML, and an analysis of relevant available postmarketing surveillance data.

show abstract

“…In patients who underwent BM transplantation and resumed gilteritinib, the most frequent AEs included diarrhea (40%) and one case of fatal acute GI graft-versus-host disease (GVHD) [29].…”

Section: Discussionmentioning

confidence: 99%

Severe Gastrointestinal Toxicity Following the Use of Gilteritinib: A Case Series and Analysis of Postmarketing Surveillance Data

Gozzo,

Nardo,

Brancati

et al. 2023

Healthcare

View full text Add to dashboard Cite

show abstract

“…Grade 3 acute graft-vs.-host disease occurrences and associated mortality were infrequent. Overall, post-transplantation survival in the two study arms was comparable [40]. Recently the MD Anderson group reported the data of a retrospective analysis of adult patients with FLT3-ITD AML who underwent HSCT and thereafter received sorafenib or gilteritinib as post-transplant maintenance.…”

Section: Maintenance Therapy With Gilteritinib After Allogenic Transp...mentioning

confidence: 97%

Gilteritinib: The Story of a Proceeding Success into Hard-to-Treat FLT3-Mutated AML Patients

Molica

Perrone

Rossi

2023

JCM

View full text Add to dashboard Cite

The traditionally dismal outcome of acute myeloid leukemia (AML) patients carrying the FMS-related tyrosine kinase 3 (FLT3) mutations has been mitigated by the recent introduction of tyrosine kinase inhibitors (TKI) into clinics, such as midostaurin and gilteritinib. The present work summarizes the clinical data that led to the use of gilteritinib in clinical practice. Gilteritinib is a second-generation TKI with deeper single-agent activity than first-generation drugs against both FLT3FLT3–ITD and TKD mutations in human studies. Moreover, the phase I/II dose-escalation, dose-expansion Chrysalis trial showed an acceptable safety profile of gilteritinib (diarrhea, elevated aspartate aminotransferase, febrile neutropenia, anemia, thrombocytopenia, sepsis, and pneumonia) and a 49% overall response rate (ORR) in 191 FLT3FLT3-mutated relapsed/refractory (R/R) AML patients. In 2019, the pivotal ADMIRAL trial showed that the median overall survival was significantly longer in patients treated with gilteritinib than among those receiving chemotherapy (9.3 vs. 5.6 months, respectively) and the ORR to gilteritinib was 67.6%, outperforming the 25.8% for chemotherapy arm and leading to the license for its clinical use by the US Food and Drug Administration. Since then, several real-world experiences have confirmed the positive results in the R/R AML setting. Finally, gilteritinib-based combinations currently under investigation, with several compounds (venetoclax, azacitidine, conventional chemotherapy, etc.) and some practical tips (maintenance after allogeneic transplantation, interaction with antifungal drugs, extramedullary disease, and onset of resistance), will be analyzed in detail in this review.

show abstract

“…A follow-up to the ADMIRAL trial reported that 18 of 26 long-term survivors without relapse in the gilteritinib arm proceeded to alloHSCT, with 16 of 18 re-starting gilteritinib in the post-alloHSCT setting ( 105 ). In a report focusing on post-alloHSCT outcomes in the ADMIRAL trial, patients who resumed gilteritinib and had a CR had low relapse rates (20% for those in CRc, 0% for those in CR) ( 106 ). The unpublished phase III MORPHO study (BMT CTN 1506) randomized 356 patients to two years of gilteritinib (120mg per day) starting 30-90 days post-alloHSCT vs placebo in adults with FLT3- ITD AML in CR1.…”

Section: Targeted Therapy In the Post-transplant Settingmentioning

confidence: 99%

Innovations in conditioning and post-transplant maintenance in AML: genomically informed revelations on the graft-versus-leukemia effect

Murdock,

Ho,

Garcia

2024

Front. Immunol.

View full text Add to dashboard Cite

Acute Myeloid Leukemia (AML) is the prototype of cancer genomics as it was the first published cancer genome. Large-scale next generation/massively parallel sequencing efforts have identified recurrent alterations that inform prognosis and have guided the development of targeted therapies. Despite changes in the frontline and relapsed standard of care stemming from the success of small molecules targeting FLT3, IDH1/2, and apoptotic pathways, allogeneic stem cell transplantation (alloHSCT) and the resulting graft-versus-leukemia (GVL) effect remains the only curative path for most patients. Advances in conditioning regimens, graft-vs-host disease prophylaxis, anti-infective agents, and supportive care have made this modality feasible, reducing transplant related mortality even among patients with advanced age or medical comorbidities. As such, relapse has emerged now as the most common cause of transplant failure. Relapse may occur after alloHSCT because residual disease clones persist after transplant, and develop immune escape from GVL, or such clones may proliferate rapidly early after alloHSCT, and outpace donor immune reconstitution, leading to relapse before any GVL effect could set in. To address this issue, genomically informed therapies are increasingly being incorporated into pre-transplant conditioning, or as post-transplant maintenance or pre-emptive therapy in the setting of mixed/falling donor chimerism or persistent detectable measurable residual disease (MRD). There is an urgent need to better understand how these emerging therapies modulate the two sides of the GVHD vs. GVL coin: 1) how molecularly or immunologically targeted therapies affect engraftment, GVHD potential, and function of the donor graft and 2) how these therapies affect the immunogenicity and sensitivity of leukemic clones to the GVL effect. By maximizing the synergistic action of molecularly targeted agents, immunomodulating agents, conventional chemotherapy, and the GVL effect, there is hope for improving outcomes for patients with this often-devastating disease.

show abstract

Outcomes in Patients with FLT3-Mutated Relapsed/ Refractory Acute Myelogenous Leukemia Who Underwent Transplantation in the Phase 3 ADMIRAL Trial of Gilteritinib versus Salvage Chemotherapy

Cited by 21 publications

References 27 publications

Severe Gastrointestinal Toxicity Following the Use of Gilteritinib: A Case Series and Analysis of Postmarketing Surveillance Data

Severe Gastrointestinal Toxicity Following the Use of Gilteritinib: A Case Series and Analysis of Postmarketing Surveillance Data

Gilteritinib: The Story of a Proceeding Success into Hard-to-Treat FLT3-Mutated AML Patients

Innovations in conditioning and post-transplant maintenance in AML: genomically informed revelations on the graft-versus-leukemia effect

Contact Info

Product

Resources

About