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Is Targeted Therapy better than Chemotherapy for Relapsed FLT3-Mutated Acute Myeloid Leukemia?

Jan 8, 2020


In relapsed and refractory AML with poor 5 year survival of only 25%, a clinical study comparing targeted therapy with salvage cytotoxic chemotherapy showed targeted treatment based on genomic and molecular profiling can have better outcomes with lower frequency of adverse events, when compared to chemotherapy.

Acute Myeloid Leukemia (AML) is a cancer of the blood and bone marrow cells and mainly affects adults. AML is characterized by the uncontrolled and excessive growth of immature blood forming myeloblast cells in the bone marrow that crowd out the normal blood cells. The goal of AML treatment is to eliminate all the abnormal leukemia cells and get the patient in remission. However, in many cases, if all the leukemia cells were not wiped out by the treatment, the disease can relapse post being in remission for sometime. In some patients, the leukemia is resistant to the standard of care chemotherapy treatment and is considered refractory.

Targeted Therapy or Chemotherapy in AML

Which is better – Targeted Therapy or Chemotherapy ?

In cases of relapsed or refractory AML, genomic profiling of the tumor gives more insights into the molecular characteristics underlying the cancer that can then be treated with more targeted therapies. One such genetic abnormality found in 30% of AML patients is FMS-like tyrosine kinase 3 (FLT3) receptor, if present, is a disease driver and cause for resistance to chemotherapy (Papaemmanuil E et al, New Engl. J Med., 2016). There are 2 main kinds of FLT3 genomic abnormalities that have been found in AML genomes: a tandem duplication of the FLT3 gene (ITD) or mutations in the tyrosine kinase domain of the FLT3 gene (TKD). Both aberrations result in an overactivation of the FLT3 receptor signaling pathway that drives the uncontrolled growth of the leukemia and makes it resistant to standard of care chemotherapy options. The toolbox of targeted drugs with varying selectivity, potency and clinical activity, that have been approved or in development for FLT3 mutated AML are:

  • Midostaurin, a multi-targeted drug, is approved in combination with the standard 7+3 (cytarabine + daunorubicin) chemotherapy for patients that are newly diagnosed with AML with FLT3 mutation. But for patients with relapsed or refractory AML, midostaurin has not shown a lasting clinical benefit as a single agent. (Stone RM et al, New Engl. J Med., 2017; Fisher T, et al, J Clin Oncol., 2010)
  • Sorafenib, another multi-kinase targeting drug, has shown clinical activity in patients with FLT3-mutated AML. (Borthakur G, et al, Haematologica, 2011)
  • Quizartinib, a new class of targeted FLT3 inhibitor showed some single-agent activity in relapsed and refractory patients with FLT3-ITD but the response was short lived due to not targeting FLT3 TKD mutations that can arise during treatment. (Cortes JE et al, Lancet Oncol., 2019)
  • Gilteritinib is another new class of drug in clinical development, that is selective for both ITD and TKD mutations. In a phase 1-2 clinical study, 41% of patients with relapsed and refractory AML had a complete remission.(Perl AE, et al, Lancet Oncol., 2017)

Science of Right Personalized Nutrition for Cancer

A phase 3 randomized clinical trial compared the impact of the targeted therapy Gilteritinib vs. salvage chemotherapy in 371 relapsed and refractory AML patients (Trial No. NCT02421939). Of the 371 relapsed and refractory AML patients, 247 were randomly assigned to the Gilteritinib group and 124 to the salvage chemotherapy group. The ratio of relapsed and refractory in both groups was approximately 60:40. The salvage chemotherapy options were either high intensity treatments: Mitoxantrone, Etoposide, Cytarabine (MEC), or Fludarabine, Cytarabine, Granulocyte colony-stimulating factor and Idarubicin (FLAG-IDA); or low intensity treatment options: low-dose Cytarabine, or Azacitidine. Recently published results of this trial showed that the targeted treatment group with Gilteritinib had an overall survival of 9.3 months when compared to the 5.6 months with the salvage chemotherapy group. There were 34% patients who achieved complete remission with partial or complete hematologic recovery in the Gilteritinib group, while only 15.3% in the chemotherapy group. Also, severe adverse events of grade 3 or higher were found to occur less frequently in the targeted group over the chemotherapy group (Perl AE, et al, New Engl. J Med., 2019).

The above data supports that in this difficult to treat relapsed and refractory AML with a poor prognosis and 5 year survival of only 25%, targeted treatment based on genomic and molecular profiling can have better outcomes with lower frequency of adverse events, when compared to continued chemotherapy treatments.

Cancer patients often have to deal with different chemotherapy side effects which affect their quality of life and look out for alternative therapies for cancer. Taking the right nutrition and supplements based on scientific considerations (avoiding guesswork and random selection) is the best natural remedy for cancer and treatment related side-effects.