Clinical practice recommendation on hematopoietic stem cell transplantation for acute myeloid leukemia patients with <i>FLT3</i>-internal tandem duplication: a position statement from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Bazarbachi, Ali; Bug, Gesine; Baron, Frédéric; Brissot, Éolia; Ciceri, Fabio; Dalle, Iman Abou; Döhner, Hartmut; Esteve, Jordi; Fløisand, Yngvar; Giebel, Sebastian; Gilleece, Maria; Gorin, Norbert Claude; Jabbour, Elias; Aljurf, Mahmoud; Kantarjian, Hagop M.; Kharfan‐Dabaja, Mohamed A.; Labopin, Myriam; Lanza, Francesco; Malard, Florent; Perić, Zinaida; Prébet, Thomas; Ravandi, Farhad; Ruggeri, Annalisa; Sanz, Jaime; Schmid, Christoph; Shouval, Roni; Spyridonidis, Alexandros; Versluis, Jurjen; Vey, Norbert; Savani, Bipin N.; Nagler, Arnon; Mohty, Mohamad

doi:10.3324/haematol.2019.243410

Cited by 106 publications

(99 citation statements)

References 120 publications

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“…This score clearly separated patients into 3 groups with different outcomes: patients in groups 1 and 2, e.g., those with late molecular relapse who had promising CR and 2-year OS rates of 71% and 64%, respectively; patients in group 3 with early hematologic relapse exhibited CR and 2-year OS rates of 29% and 27%, suggesting that in these patients alternative strategies such as addition of a second compound (i.e., Lenalidomide [ 31 , 32 ], Venetoclax [ 33 ]) or investigational agents might improve their prognosis. Furthermore, the currently available FLT3 inhibitors such as Gilteritinib or Sorafenib may represent alternatives, either alone or in combination with Aza, for patients with FLT3 mutation at relapse, which was the case in 11 of 38 of our patients tested at relapse [ 25 , 34 , 35 ]. A previously reported score was developed exclusively in patients with hematological relapse and incorporated the interval between transplant and relapse and the BM blast count at relapse [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

Prediction of Response and Survival Following Treatment with Azacitidine for Relapse of Acute Myeloid Leukemia and Myelodysplastic Syndromes after Allogeneic Hematopoietic Stem Cell Transplantation

Rautenberg

Bergmann

Germing

et al. 2020

Cancers

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To provide long-term outcome data and predictors for response and survival, we retrospectively analyzed all 151 patients with relapse of myeloid neoplasms after allogeneic hematopoietic stem cell transplantation (allo-HSCT) who were uniformly treated with first-line azacitidine (Aza) salvage therapy at our center. Patients were treated for molecular (39%) or hematologic relapse (61%), with a median of 5 cycles of Aza and at least one donor lymphocyte infusion in 70% of patients. Overall response was 46%, with 41% achieving complete (CR) and 5% achieving partial remission. CR was achieved after a median of 4 cycles and lasted for a median of 11 months (range 0.9 to 120 months). With a median follow-up of 22 months (range: 1 to 122 months), the 2-year survival rate was 38% ± 9%, including 17 patients with ongoing remission for >5 years. Based on results from multivariate analyses, molecular relapse and time to relapse were integrated into a score, clearly dividing patients into 3 subgroups with CR rates of 71%, 39%, and 29%; and 2-year survival rates of 64%, 38%, and 27%, respectively. In the subgroup of MDS and secondary AML, receiving upfront transplantation was associated with superior response and survival, and therefore pretransplant strategy was integrated together with relapse type into a MDS–sAML-specific score. Overall, Aza enables meaningful responses and long-term survival, which is a predictable with a simple-to-use scoring system.

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Section: Discussionmentioning

confidence: 99%

Prediction of Response and Survival Following Treatment with Azacitidine for Relapse of Acute Myeloid Leukemia and Myelodysplastic Syndromes after Allogeneic Hematopoietic Stem Cell Transplantation

Rautenberg

Bergmann

Germing

et al. 2020

Cancers

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“…In a recent position statement by the European Society for Blood and Marrow Transplantation (EBMT), HCT in first CR was recommended for patients with intermediate or adverse risk FLT3- ITD AML and could be considered in low risk disease. Furthermore, in the absence of GVHD, post-HCT FLT3 inhibitor maintenance was recommended, ideally on a clinical trial ( 141 ). Randomized trials are needed to further clarify these algorithms.…”

Section: Ongoing Questions and Controversiesmentioning

confidence: 99%

FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies

2020

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The FLT3 receptor is overexpressed on the majority of acute myeloid leukemia (AML) blasts. Mutations in FLT3 are the most common genetic alteration in AML, identified in approximately one third of newly diagnosed patients. FLT3 internal tandem duplication mutations (FLT3-ITD) are associated with increased relapse and inferior overall survival. Multiple small molecule inhibitors of FLT3 signaling have been identified, two of which (midostaurin and gilteritinib) are currently approved in the United States, and many more of which are in clinical trials. Despite significant advances, resistance to FLT3 inhibitors through secondary FLT3 mutations, upregulation of parallel pathways, and extracellular signaling remains an ongoing challenge. Novel therapeutic strategies to overcome resistance, including combining FLT3 inhibitors with other antileukemic agents, development of new FLT3 inhibitors, and FLT3-directed immunotherapy are in active clinical development. Multiple questions regarding FLT3-mutated AML remain. In this review, we highlight several of the current most intriguing controversies in the field including the role of FLT3 inhibitors in maintenance therapy, the role of hematopoietic cell transplantation in FLT3-mutated AML, use of FLT3 inhibitors in FLT3 wild-type disease, significance of non-canonical FLT3 mutations, and finally, emerging concerns regarding clonal evolution.

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“…Acute Leukemia Working Party of the EBMT published a very recent clinical practice recommendation on allo-HSCT in AML patients with FLT3-ITD (105). The group recommends posttransplant maintenance with sorafenib in all cases except in patients with active acute GVHD.…”

Section: Flt3 Inhibitors As Maintenance Therapymentioning

confidence: 99%

Pharmacologic Therapies to Prevent Relapse of Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation

et al. 2020

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Relapse is the main cause of mortality in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Adverse cytogenetic or molecular risk factors, as well as refractory disease or persistent measurable residual disease (MRD) at the time of transplantation are associated with an increased risk of recurrence. Salvage therapy for AML relapse after allo-HSCT is often limited to chemotherapy, donor lymphocyte infusions and/or second transplants and is rarely successful. Effective post-transplant preventive intervention in high risk AML may be crucial. The most frequent and promising approach is the use of post-transplant maintenance with hypomethylating agents or with FLT3 tyrosine kinase inhibitors when the target is present. Moreover, IDH1/IDH2 inhibitors and BCL-2 inhibitors in combination with other strategies are promising approaches in the maintenance setting. Here we summarize the current knowledge about the preemptive and prophylactic use of pharmacologic agents after allo-HSCT to prevent relapse of AML.

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Clinical practice recommendation on hematopoietic stem cell transplantation for acute myeloid leukemia patients with FLT3-internal tandem duplication: a position statement from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Cited by 106 publications

References 120 publications

Prediction of Response and Survival Following Treatment with Azacitidine for Relapse of Acute Myeloid Leukemia and Myelodysplastic Syndromes after Allogeneic Hematopoietic Stem Cell Transplantation

Prediction of Response and Survival Following Treatment with Azacitidine for Relapse of Acute Myeloid Leukemia and Myelodysplastic Syndromes after Allogeneic Hematopoietic Stem Cell Transplantation

FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies

Pharmacologic Therapies to Prevent Relapse of Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation

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