September 2021 Clinical Case of the Month
Title: Role of maintenance therapy following allogeneic transplantation in AML
Submitted by: Syed Ali Abutalib and Nicolaus Kröger
Physicians expert perspective: Andreas Burchert
61-year-old female with FLT3-ITD acute myeloid leukemia undergoes successful HLA-MSD myeloablative allogeneic hematopoietic cell transplantation (allo-HCT). Prior to allo-HCT, she was treated for relapsed disease on a clinical trial with triple therapy – venetoclax, decitabine and gilteritinib and luckily achieved complete molecular-FLT3-ITD negative- remission.
Currently, she is 40 days after allo-HCT and on prophylactic tacrolimus. She does not have graft versus host disease or infection. The comprehensive metabolic profile, complete blood count with differential and bone marrow examination are all unremarkable. The FLT3-ITD mutation continues to be undetected in the marrow aspirate. The sorted, CD33 and CD3 chimera are 100% of donor origin. Given the high risk for disease relapse, few of the transplant team members advocate for prophylactic maintenance therapy.
Based on available data, which of the following is most appropriate recommendation?
A. Initiate decitabine
B. Initiate venetoclax and azacytidine
C. Initiate sorafenib
D. Initiate gilteritinib
E. Maintenance therapy is not warranted
Expert Perspective by Professor Dr. Andreas Burchert
This particular patient has a high risk of relapse in the range of 50% even after allogeneic hematopoietic stem cell transplantation (allo-HCT). Of importance, the relapse risk might be slightly lower than 50%, given MRD-negativity prior to allo-HCT 1. However, whether MRD negativity that is achieved with an experimental treatment as in this patient, is biologically equivalent to MRD-negativity that is achieved using conventional induction chemotherapy such as 7+3, is unknown. Nevertheless, also a relapse risk below 50% poses a considerable risk of death through AML and thus represents an unmet medical need.
The narrative of maintenance therapy after allo-HCT as a measure to prevent relapse is not novel. However, so far, the evidence for efficacy was weak. For example, small uncontrolled studies supported the use of decitabine - a hypomethylating agent (HMA) - as maintenance therapy after allo-HCT2. Also the use of an alternative HMA, azacytidine, has been studied as maintenance therapy after allo-HCT 3,4,5. However, although interesting, at this time being, these uncontrolled or retrospective studies cannot justify a post allo-HCT HMA maintenance as a routine clinical strategy.
A recently published double blind and placebo controlled trial, VIALE A, showed that Venetoclax in combination with a azacytidine improves survival in elderly AML patients who cannot tolerate intensive induction chemotherapy6. Although this clearly implies efficacy of a venetoclax-based maintenance as post allo-HCT therapy approach, such treatment cannot be recommended as routine concept before data from a randomized post allo-HCT maintenance trial becomes available (e.g., VIALE-T study -ClinicalTrials.gov Identifier: NCT04161885).
Likewise, there are currently no data from randomized controlled trials to support the use of gilteritinib - a FLT3- and AXL- tyrosine kinase inhibitor, which has been approved for the treatment of relapsed and refractory AML with activating FLT3-mutations but not for post allo-HCT maintenance therapy7. The pivotal Astellas-sponsored MORPHO trial, addressing the value of a gilteritinib maintenance therapy post allo-HCT is currently ongoing with results being expected in 2025 (ClinicalTrials.gov Identifier: NCT02997202 )8. Midostaurin, a first generation FLT3-TKI, has been approved for the first line therapy of FLT3-mutated AML, but not as maintenance drug post allo-HCT9. In fact, a post allo-HCT trial randomizing midostaurin versus conventional care did not show evidence for improved outcome with midostaurin 10.
Two recent prospectively controlled randomized trials have shown a benefit from sorafenib maintenance after allo-HCT: i) the placebo-controlled SORMAIN trial and ii) an open label phase 3 trial from China. Both trials demonstrated that sorafenib maintenance post allo-HCT improves progression free- and overall- survival in FLT3-ITD positive AML 11,12. The primary endpoint in SORMAIN and the Chinese trial was relapse free survival (RFS). After a median follow-up of 41.8 months in SORMAIN, median RFS was not reached with sorafenib versus 30.9 months with placebo (HR 0.39, 95% CI 0.18–0.85; P = 0.013). Sorafenib reduced the risk of relapse or death by 75% (HR 0.25, P=0.002) in SORMAIN11. In the Chinese phase 3 trial, the median follow-up duration is 21.3 months. The 2-year leukemia-free survival was 78.9% versus 56.6% (HR 0.37, 95% CI 0.22–0.63; P <0.0001). At 24 months, OS was higher with sorafenib versus placebo in SORMAIN (90.5% versus 66.2%; HR 0.24, 95% CI 0.08–0.74; P = 0.007) and also the phase 3 trial (82.1% versus 68.0%, HR 0.48, 95% CI 0.27–0.86; P = 0.012) 11,12. Thus, for FLT3-ITD mutated AML, there is strong evidence for a post allo- HCT maintenance therapy with sorafenib (off label) making choice C as correct answer.
Correct Answer - C
- Short, N. J. et al. Association of Measurable Residual Disease With Survival Outcomes in Patients With Acute Myeloid Leukemia: A Systematic Review and Meta-analysis. JAMA Oncol 6, 1890–1899 (2020).
- Pusic, I. et al. Maintenance Therapy with Decitabine after Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndrome. Biol. Blood Marrow Transplant. 21, 1761–1769 (2015).
- de Lima, M. et al. Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study. Cancer 116, 5420–5431 (2010).
- Platzbecker, U. et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia 26, 381–389 (2012).
- Platzbecker, U. et al. Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial. Lancet Oncol. 19, 1668–1679 (2018).
- DiNardo, C. D. et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N. Engl. J. Med. 383, 617–629 (2020).
- Perl, A. E. et al. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N. Engl. J. Med. 381, 1728–1740 (2019).
- Levis, M. J. et al. A phase 3, trial of gilteritinib, as maintenance therapy after allogeneic hematopoietic stem cell transplantation in patients with FLT3-ITD+ AML. Journal of Clinical Oncology 36, TPS7075–TPS7075 (2018).
- Stone, R. M. et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N. Engl. J. Med. 377, 454–464 (2017).
- Maziarz, R. T. et al. Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia. Bone Marrow Transplant. 129, 424–10 (2020).
- Burchert, A. et al. Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With FLT3-Internal Tandem Duplication Mutation (SORMAIN). J. Clin. Oncol. 39, 1412-1413 (2021).
- Xuan, L. et al. Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. Lancet Oncol. 21, 1201–1212 (2020).
Syed Ali Abutalib, MD
Associate Director, Hematology and Cellular Therapy Program
Director, Clinical Apheresis Program
Cancer Treatment Centers of America, Zion, Illinois
Associate Professor, Rosalind Franklin University of Medicine and Science
Nicolaus Kröger, MD
Professor and Medical Director of the Department of Stem Cell
Transplantation at the University Hospital Hamburg-Eppendorf, Germany
University Hospital Hamburg, Hamburg, Germany
Correspondence: Nicolaus Kröger, MD
Andreas Burchert, MD
Professor of Medicine
Director, Cellular Therapy Unit at the Carreras Leukemia Center
University Hospital Gießen and Marburg, Campus Marburg
Philipps University of Marburg
Future Clinical Case of the Month
If you have a suggestion for future clinical case to feature, please contact Nicolaus Kröger.