The Gut Microbiome in FLT3-ITD+ AML Undergoing Allo-HSCT With Or Without Sorafenib Maintenance After Allo-HSCT

Allogeneic Hematopoietic Stem Cell Transplantation Clinical Trial

Official title:

The Gut Microbiome Changes in FMS-like Tyrosine Kinase 3 (FLT3)-ITD Positive Acute Myeloid Leukemia Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation With or Without Sorafenib Maintenance Post-transplantation

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05596981
• Other study ID #: Microbiota-Sora-FLT3+AML-2022
• Status: Recruiting
• Start date: October 1, 2022
• Est. completion date: December 31, 2024

Study information

• Verified date: October 2022
• Source: Nanfang Hospital of Southern Medical University
• Contact: Li Xuan, MD
• Phone: +86-020-62787883
• Email: 356135708[@]qq.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This prospective trial investigates the effect of sorafenib maintenance therapy in FLT3-ITD AML patients after allo-HSCT in terms of gut microbiome.

Description:

Hematopoietic stem cell transplantation (HSCT) is used as a potentially curative therapy for patients with hematopoietic malignancies. Sorafenib, an inhibitor of multiple kinases including FLT3, has shown promising activity in FLT3-ITD-positive AML. Our previous studies demonstrated that sorafenib maintenance post-transplantation could improve the outcomes of FLT3-ITD-positive AML patients, which is associated with sorafenib enhancing the graft-versus-leukemia (GVL) effect. Recent studies show that gut microbiome is associated with graft-versus-host-disease (GVHD) and GVL. However, the exact mechanism of sorafenib enhancing the GVL effect and the influence of gut microbiome on sorafenib maintenance after allo-HSCT remain unknown.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: December 31, 2024
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• FLT3-ITD Positive AML

• Allo-HSCT Recipients

Exclusion Criteria:

• Intolerance to sorafenib pre-transplantation

• Cardiac dysfunction (particularly congestive heart failure)

• Hepatic abnormalities (bilirubin = 3 mg/dL, aminotransferase> 2 times the upper limit of normal)

• Renal dysfunction (creatinine clearance rate < 30 mL/min)

• Any abnormality in a vital sign (e.g., heart rate, respiratory rate, or blood pressure)

• Patients with any conditions not suitable for the trial (according to the investigators' decision)

Related Conditions & MeSH terms

• Acute Myeloid Leukemia With FLT3/ITD Mutation
• Allogeneic Hematopoietic Stem Cell Transplantation
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Sorafenib
The initial dose of sorafenib is 400 mg orally twice daily and is adjusted in case of suspected toxicity or resistance (dose range, 200-800 mg daily).

Locations

Country	Name	City	State
China	Department of Hematology,Nanfang Hospital, Southern Medical University	Guangzhou	Guangdong

Sponsors (1)

Lead Sponsor	Collaborator
Nanfang Hospital of Southern Medical University

Country where clinical trial is conducted

China, 

References & Publications (6)

Andrews MC, Duong CPM, Gopalakrishnan V, Iebba V, Chen WS, Derosa L, Khan MAW, Cogdill AP, White MG, Wong MC, Ferrere G, Fluckiger A, Roberti MP, Opolon P, Alou MT, Yonekura S, Roh W, Spencer CN, Curbelo IF, Vence L, Reuben A, Johnson S, Arora R, Morad G, Lastrapes M, Baruch EN, Little L, Gumbs C, Cooper ZA, Prieto PA, Wani K, Lazar AJ, Tetzlaff MT, Hudgens CW, Callahan MK, Adamow M, Postow MA, Ariyan CE, Gaudreau PO, Nezi L, Raoult D, Mihalcioiu C, Elkrief A, Pezo RC, Haydu LE, Simon JM, Tawbi HA, McQuade J, Hwu P, Hwu WJ, Amaria RN, Burton EM, Woodman SE, Watowich S, Diab A, Patel SP, Glitza IC, Wong MK, Zhao L, Zhang J, Ajami NJ, Petrosino J, Jenq RR, Davies MA, Gershenwald JE, Futreal PA, Sharma P, Allison JP, Routy B, Zitvogel L, Wargo JA. Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade. Nat Med. 2021 Aug;27(8):1432-1441. doi: 10.1038/s41591-021-01406-6. Epub 2021 Jul 8. — View Citation

Han L, Zhao K, Li Y, Han H, Zhou L, Ma P, Fan Z, Sun H, Jin H, Jiang Z, Liu Q, Peng J. A gut microbiota score predicting acute graft-versus-host disease following myeloablative allogeneic hematopoietic stem cell transplantation. Am J Transplant. 2020 Apr;20(4):1014-1027. doi: 10.1111/ajt.15654. Epub 2019 Dec 12. — View Citation

Peled JU, Devlin SM, Staffas A, Lumish M, Khanin R, Littmann ER, Ling L, Kosuri S, Maloy M, Slingerland JB, Ahr KF, Porosnicu Rodriguez KA, Shono Y, Slingerland AE, Docampo MD, Sung AD, Weber D, Alousi AM, Gyurkocza B, Ponce DM, Barker JN, Perales MA, Giralt SA, Taur Y, Pamer EG, Jenq RR, van den Brink MRM. Intestinal Microbiota and Relapse After Hematopoietic-Cell Transplantation. J Clin Oncol. 2017 May 20;35(15):1650-1659. doi: 10.1200/JCO.2016.70.3348. Epub 2017 Mar 15. — View Citation

Peled JU, Gomes ALC, Devlin SM, Littmann ER, Taur Y, Sung AD, Weber D, Hashimoto D, Slingerland AE, Slingerland JB, Maloy M, Clurman AG, Stein-Thoeringer CK, Markey KA, Docampo MD, Burgos da Silva M, Khan N, Gessner A, Messina JA, Romero K, Lew MV, Bush A, Bohannon L, Brereton DG, Fontana E, Amoretti LA, Wright RJ, Armijo GK, Shono Y, Sanchez-Escamilla M, Castillo Flores N, Alarcon Tomas A, Lin RJ, Yáñez San Segundo L, Shah GL, Cho C, Scordo M, Politikos I, Hayasaka K, Hasegawa Y, Gyurkocza B, Ponce DM, Barker JN, Perales MA, Giralt SA, Jenq RR, Teshima T, Chao NJ, Holler E, Xavier JB, Pamer EG, van den Brink MRM. Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation. N Engl J Med. 2020 Feb 27;382(9):822-834. doi: 10.1056/NEJMoa1900623. — View Citation

Sidaway P. Intestinal microbiota predict HSCT outcome. Nat Rev Clin Oncol. 2020 May;17(5):275. doi: 10.1038/s41571-020-0351-9. — View Citation

Spencer CN, McQuade JL, Gopalakrishnan V, McCulloch JA, Vetizou M, Cogdill AP, Khan MAW, Zhang X, White MG, Peterson CB, Wong MC, Morad G, Rodgers T, Badger JH, Helmink BA, Andrews MC, Rodrigues RR, Morgun A, Kim YS, Roszik J, Hoffman KL, Zheng J, Zhou Y, Medik YB, Kahn LM, Johnson S, Hudgens CW, Wani K, Gaudreau PO, Harris AL, Jamal MA, Baruch EN, Perez-Guijarro E, Day CP, Merlino G, Pazdrak B, Lochmann BS, Szczepaniak-Sloane RA, Arora R, Anderson J, Zobniw CM, Posada E, Sirmans E, Simon J, Haydu LE, Burton EM, Wang L, Dang M, Clise-Dwyer K, Schneider S, Chapman T, Anang NAS, Duncan S, Toker J, Malke JC, Glitza IC, Amaria RN, Tawbi HA, Diab A, Wong MK, Patel SP, Woodman SE, Davies MA, Ross MI, Gershenwald JE, Lee JE, Hwu P, Jensen V, Samuels Y, Straussman R, Ajami NJ, Nelson KC, Nezi L, Petrosino JF, Futreal PA, Lazar AJ, Hu J, Jenq RR, Tetzlaff MT, Yan Y, Garrett WS, Huttenhower C, Sharma P, Watowich SS, Allison JP, Cohen L, Trinchieri G, Daniel CR, Wargo JA. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response. Science. 2021 Dec 24;374(6575):1632-1640. doi: 10.1126/science.aaz7015. Epub 2021 Dec 23. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Variation of Gut Microbiota Composition and Diversity	Variation of gut microbiota composition and diversity, as determined by 16s rRNA sequencing of serial stool samples, during Sorafenib Maintenance Therapy.	3 months
Secondary	Variation of gut barrier integrity	As determined by serum levels of zonulin, I-FABP, and citrulline or other potential candidates.	3 months
Secondary	NRM	Non-relapse mortality (NRM)	1 year
Secondary	Acute GVHD	Acute Graft-Versus-Host-Disease	100 days
Secondary	Chronic GVHD	Chronic Graft-Versus-Host-Disease	1 year
Secondary	AEs	Adverse Events	1 year
Secondary	OS	Overall survival	1 year
Secondary	LFS	Leukemia-free survival	1 year
Secondary	Relapse	Cumulative incidence of relapse	1year