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During the 2nd How to Diagnose and Treat Acute Leukaemia conference of the European School of Haematology (ESH), our AML Hub Executive Steering Committee member, Jorge Sierra, delivered an oral presentation on the addition of midostaurin to frontline cytarabine plus the anthracycline, idarubicin (7+3) for the treatment of acute myeloid leukemia (AML), with a focus on a case report.1 This is the first in a series of case reports about the addition of a third agent to frontline 7+3.
Approximately a third of patients with AML have FLT3-ITD or tyrosine kinase domain (TKD) mutations, which lead to constitutive activation of FLT3, thus increasing proliferation and driving resistance to chemotherapy and apoptosis. FLT3 mutations are associated with a high WBC count and relapse rate. Midostaurin is Type I FLT3 inhibitor (non-specific and effective against both TKD and ITD mutations).1 |
During the 61st American Society of Hematology (ASH) Meeting & Exposition in Orlando, US, 2019, Jorge Sierra presented data (previously reported on the AML Hub) that demonstrated patients with intermediate cytogenetics (according to the Medical Research Council classification), with an NPM1 mutation and low allelic ratio of FLT3-ITD, had a similar outcome compared with those who had an NPM1 mutation without FLT3 mutation (74 ± 9% and 66 ± 18%, respectively). Moreover, those with an NPM1 mutation and high FLT3-ITD allelic ratio had a very poor prognosis (26 ± 16%).1 |
The patient’s management plan is demonstrated in Figure 1 and discussed in more detail below.
Figure 1. Treatment management plan1
Blue arrows indicate response to treatment.
Minimal residual disease was measured by flow cytometry and NPM1 copy number.
CR, complete remission; G-CSF, granulocyte-colony stimulating factor; MRD -ve, minimal residual disease negativity; HiDAC, high dose cytarabine; HSCT, hematopoietic stem cell transplant
This treatment regimen was based on the AML-12 trial of the Spanish CETLAM group (previously reported on the AML Hub), where 77% of patients achieved a complete response.3 |
ELN 2017 treatment approach for patients ≤ 60–65 years stated an induction therapy of 7+3 (cytarabine + anthracycline), with high doses of cytarabine generally considered as the best treatment option for those not responding to the first cycle of 7+3. Those with newly diagnosed AML and activating FLT3 mutations were also considered to receive additional therapy with midostaurin following chemotherapy. (These guidelines were accepted before the approval of midostaurin by the U.S. Food and Drug Administration [FDA] and European Medicines Agency [EMA]).1,2 |
Current National Comprehensive Cancer Network (NCCN) guidelines V3.2020 state the use of standard dose cytarabine 200 mg/m2 continuous infusion for 7 days, with idarubicin 60 mg/m2 for 3 days, and oral midostaurin at 50 mg every 12 hours from Days 8–21 for those with FLT3-mutated AML.1 |
The use of midostaurin in first line treatment was based on the phase III RATIFY study (previously reported by the AML Hub), where there was a 24.3% lower risk of death in the midostaurin group than in the placebo group.1,4 |
The patient responded to induction therapy, with a complete remission (CR) with minimal residual disease (MRD) negativity by flow cytometry and NPM1 copy number.
The patient then received first consolidation with high dose cytarabine (HiDAC; 3 g/m2) plus midostaurin on Days 8–21, and remained in CR with MRD negativity. He was given a second consolidation with the same treatment, and subsequently remained MRD-negative and in CR. As the patient was in first complete remission (CR1), he was eligible for a hematopoietic stem cell transplantation (HSCT).
The ELN 2017 guidelines state that consolidation treatment for patients with intermediate risk genetics should be allogeneic HSCT, or intermediate dose cytarabine (IDAC), or HiDAC with autologous HSCT. Allogeneic HSCT in CR1 is the most favorable treatment option.1 |
However, the donor experienced a splenic rupture, and therefore peripheral blood stem cell mobilization and collection were cancelled.
The patient received a haploidentical HSCT from his daughter.
The phase II DE02T trial (AMLSG 16-10) (previously reported on the AML Hub) assessed the effect of midostaurin in combination with HiDAC with subsequent allogeneic HSCT, and demonstrated that midostaurin significantly improved event free survival (HR, 0.58; 95% CI, 0.48–0.70; P < 0.001).5 |
The RADIUS phase II study (previously reported on the AML Hub) examined the use of a midostaurin combination with standard of care (SOC) as maintenance after allogeneic HSCT. The study showed no significant improvement with midostaurin posttransplant, although there was a 54% relative reduction in the risk of relapse compared with SOC.1 |
Although FLT3-ITD usually confers poor prognosis, midostaurin improves overall survival when added to intensive front-line chemotherapy followed by maintenance. Jorge Sierra concluded that the best treatment strategy in fit young patients with FLT3-ITD-mutated AML is chemotherapy plus midostaurin, followed by allogeneic transplantation in CR1. This is well demonstrated by this case study, and presently the patient remains in a perfect general status (Eastern Cooperative Oncology Group status 0), with continuous CR and MRD-negativity at 3 years posttransplant, and no GvHD.
For more information on how MRD impacts the outcome of HSCT in patients with AML, follow our AML Hub Satellite Symposium. The event will take place on August 30, 2020, at 8:30 A.M. CEST, during the 46th Annual Meeting of the European Society for Blood and Marrow Transplantation, and will feature five international experts, Gert Ossenkoppele, Jacqueline Cloos, Christian Thiede, Adriano Venditti, and Charles Craddock.
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