The development of agents targeting specific mutations like CALR and JAK2V617F marks a move away from the "one size fits all" JAK inhibitor approach. This enables a more personalized, molecularly-driven treatment strategy that was previously not possible for MPN patients.

Dr. Bardia emphasizes that ESR1 is an 'acquired alteration,' meaning the mutation can develop during treatment. This necessitates a shift from one-time diagnostic testing to a dynamic, serial testing model. Repeat testing is critical to identify these actionable mutations as they arise, allowing patients to access newly approved targeted therapies.

An individual tumor can have hundreds of unique mutations, making it impossible to predict treatment response from a single genetic marker. This molecular chaos necessitates functional tests that measure a drug's actual effect on the patient's cells to determine the best therapy.

The same cancer-driving mutation behaves differently depending on the cell's internal "wiring." For example, a drug targeting a mutation works in melanoma but induces resistance in colorectal cancer due to a bypass pathway. This cellular context is why genetic data alone is insufficient.

While quizartinib's benefit is less pronounced in AML patients over 60, a specific genomic signature—the co-occurrence of FLT3-ITD, NPM1, and DNMT3A mutations—identifies a subset of older patients who derive a significant survival benefit, challenging age-based treatment decisions.

The RSClin tool integrates a patient's Oncotype DX score with their unique clinical-pathologic features, such as tumor size and grade. This provides a more accurate and personalized risk assessment, as the same genomic score can represent significantly different prognoses for patients who have low versus high clinical risk factors.

The Spanish KIWI trial showed a surprising survival benefit for quizartinib in FLT3-ITD negative AML. The benefit was greatest in patients with NPM1 and DNMT3A mutations, suggesting the drug's efficacy extends beyond its primary target through other mechanisms.

TP53-mutated AML carries an extremely poor prognosis, significantly worse than other adverse-risk subtypes. When TP53 patients are excluded from analyses, the survival gap between the remaining adverse-risk and intermediate-risk patients narrows considerably, clarifying risk stratification.

The primary goal in CML is evolving from chronic management to achieving Treatment-Free Remission (TFR). This paradigm shift favors using the most potent TKIs, like asciminib, first-line to induce deep, rapid molecular responses and enable eventual therapy discontinuation.