A modified Delphi consensus on the management of patients with relapsed or refractory FLT3-mutated acute myeloid leukemia in four Latin American countries

Abstract Introduction: In Latin America (LATAM), there is variability in the management of specific patient (pt) groups with acute myeloid leukemia (AML), likely due to unequal access to treatment options, including hematopoietic stem cell transplantation (HSCT). Over 20% of pts with AML in LATAM have FLT3 mutations (FLT3m+), which are associated with increased risk of relapse/refractoriness (R/R). Treatment of R/R FLT3m+ AML in LATAM has significantly advanced with the introduction of FLT3 tyrosine kinase inhibitor (TKI) therapies. This study aims to provide recommendations for pts with R/R FLT3m+ AML who are unfit for HSCT; are fit but not undergoing HSCT; or are receiving post-HSCT management. Methods: A modified 3-stage Delphi methodology was used; the first 2 stages involved online surveys where experts provided their responses and received aggregated feedback; the last stage involved a live discussion to agree on unresolved questions. Stages were conducted separately for each country. Surveys and discussion guides were based on a targeted literature review, followed by an independent steering committee recommendation. Categorical questions were based on Likert scale, rankings, yes/no, or multiple-choice questions; quantitative questions were open-ended. For categorical variables, agreement was reached when >80% of panelists answered “(dis)agree strongly”/”(dis)agree” in Likert scale questions, or same answer in yes/no or multiple-choice. A coefficient of variation ≤0.5 was used to assess agreement for continuous variables. Only if all 4 countries reached an alignment was it considered an agreement. Results: In total, 44 hematology specialists were invited based on predefined eligibility criteria and clinical experience, and were organized into 4 groups based on country of practice (Argentina, Chile, Colombia, Mexico; 11 in each group). For pts with R/R FLT3m+ AML unfit for HSCT, agreement was reached on treatment tolerance, reduced toxicity, disease progression control and improved quality of life as therapeutic goals. Panelists agreed on ECOG performance status ≥2, high comorbidity and KPS <70 as defining criteria for unfit pts, and on the FLT3-TKI gilteritinib as the preferred first therapeutic option. When prescribing gilteritinib, panelists agreed on continuing treatment until disease progression; absence of clinical benefit/hematologic response; or unacceptable toxicity. Panelists agreed on not interrupting or discontinuing gilteritinib in case of comedication (ie, prophylactic antifungals) or toxicity (ie, mycosis, elevated transaminases grade 2, moderate anemia [hemoglobin [Hb] 8–10g/dL], thrombocytopenia [50,000–100,000/μL], or neutropenia [500–1,000/µL]). If an unfit pt does not reach any type of complete response but shows improvement in blast count after 2 cycles of gilteritinib monotherapy, agreement was reached to maintain gilteritinib monotherapy 120mg/day up to 6 cycles. For pts with R/R FLT3m+ AML who are fit but do not undergo HSCT due to access or system limitations, panelists agreed on prolonging relapse-free survival as a therapeutic goal. Panelists agreed on gilteritinib as the preferred treatment option for induction and consolidation therapy. Panelists agreed on administering FLT3-TKI or low intensity consolidation therapy until HSCT, disease progression, unacceptable toxicity, or lack of response, and did not agree on high intensity therapy. Panelists agreed on neutrophils (<500/μL), red blood cells (hemoglobin 7-8 mg/dL), and transaminase levels (>3x ULN) as safety parameters for stopping induction or consolidation. For post-HSCT maintenance, panelists agreed on the absence of acute GvHD grade ≤2, active infection or life-threatening post-transplant complications as conditions for treatment initiation, and recommended gilteritinib as the preferred first option. Panelists agreed on resuming the same FLT3-TKI treatment for pts who received FLT3-TKI pre-HSCT. Finally, panelists agreed on unacceptable toxicity and lack of tolerability as factors for discontinuing maintenance.Conclusions: While most statements reached agreement across all 4 countries, some only reached country-level agreement; including inclusion of age when defining unfit pts; HMA+venetoclax as a preferred induction choice in fit pts; whether to combine FLT3-TKI with another agent if the fit pt has suboptimal response; duration of post-HSCT treatment; and whether MRD status is a determining factor to initiate post-HSCT treatment.