Treatment for Relapsed/Refractory Acute Myeloid Leukemia

Abstract

Patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) have a poor prognosis and treatment remains challenging. For the majority of r/r patients, allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment approach. Salvage therapy is given in order to reduce the leukemia load prior to transplantation. Patients achieving complete remission prior to allogeneic HSCT have a more favorable outcome. Intensive salvage regimens commonly consist of an anthracycline and high-dose cytarabine backbone. Donor lymphocyte infusions have shown efficacy in patients relapsing after allogeneic HSCT. For patients who cannot be intensively treated (eg, elderly AML patients), outcome is generally very poor and combinations with novel agents are currently under investigation. Mutational analysis should be repeated at the time of relapse to identify aberrations that can be targeted with new agents. For r/r AML patients with mutated fms-related tyrosine kinase 3 (FLT3), gilteritinib has shown superior results to intensive salvage regimens. The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved gilteritinib for FLT3 mutated r/r AML patients. Ivosidenib and enasidenib, inhibitors for mutated isocitrate dehydrogenase (IDH) 1 and 2, respectively, have received approval for IDH1/IDH2 mutated r/r AML by the FDA (not EMA). APR-246 restores the function of mutated TP53 and early study results are promising. Other agents targeting CD47, menin, neural-precursor-cell-expressed developmentally down-regulated 8, as well as bispecific antibodies or chimeric antigen receptor T cells are under investigation. Further trials are needed to understand how to best combine novel agents with each other or with chemotherapy.

A Clinical Phase 1B Study of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

“…The greatest challenge in the field of AML therapy is achieving deep CRs and longterm leukemia-free survival in R/R AML patients [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Despite the fact that we have…”

“…The greatest challenge in the field of AML therapy is achieving deep CRs and longterm leukemia-free survival in R/R AML patients [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Despite the fact that we have gained new insights and a better understanding of cell-intrinsic drivers of AML and new drugs have been developed for targeting select somatic mutations, the majority of R/R AML patients die of leukemia [8][9][10][11][12][13][14][15][16]. In patients at second or subsequent relapse, the median overall survival is ≤3 months, warranting the development and testing of novel therapies aimed at overcoming the drug resistance at relapse.…”

“…The rate of new cases of AML is 4.3 per 100,000 men and women per year, and the death rate is 2.8 per 100,000 men and women per year. Several targeted medicines, such as FLT3 inhibitors, IDH1/2 inhibitors, and BCL-2 inhibitor Venetoclax, as well as biotherapeutics (e.g., antibody-drug conjugates) for AML therapy have been developed and approved by the FDA over the last 10 years [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Despite these recent advances in therapy, more than 50% of patients who achieve a remission eventually relapse, and the five-year overall survival remains at 29.5%.…”

“…Despite these recent advances in therapy, more than 50% of patients who achieve a remission eventually relapse, and the five-year overall survival remains at 29.5%. Furthermore, the prognosis is very poor in patients who relapse after frontline induction therapy, with <10% surviving five years after the recurrence of their leukemia [8][9][10][11][12][13][14][15][16]. There is an urgent and unmet need for effective new treatment modalities for relapsed AML [8][9][10][11][12][13][14][15][16].…”

“…Furthermore, the prognosis is very poor in patients who relapse after frontline induction therapy, with <10% surviving five years after the recurrence of their leukemia [8][9][10][11][12][13][14][15][16]. There is an urgent and unmet need for effective new treatment modalities for relapsed AML [8][9][10][11][12][13][14][15][16].…”