What is the best predictor of survival in Chronic Myeloid Leukemia (CML) patients?

From the Guidelines

The best predictor of survival in Chronic Myeloid Leukemia (CML) patients is the achievement of early molecular response to tyrosine kinase inhibitor (TKI) therapy, particularly BCR-ABL1 transcript levels at 3 and 6 months after treatment initiation, as evidenced by the most recent study in 2023 1. Patients who achieve BCR-ABL1 transcript levels ≤10% at 3 months and ≤1% at 6 months (measured by quantitative PCR) have significantly better overall survival rates. This early response reflects the effectiveness of TKI therapy in suppressing the Philadelphia chromosome-positive leukemic clone. Some key points to consider include:

• The depth of molecular response continues to be important throughout treatment, with achievement of major molecular response (MMR, BCR-ABL1 ≤0.1%) and deep molecular responses (MR4, BCR-ABL1 ≤0.01% or MR4.5, BCR-ABL1 ≤0.0032%) associated with excellent long-term outcomes, as shown in studies such as the DASISION and ENESTnd trials 1.
• Other important prognostic factors include the Sokal, Hasford, or EUTOS risk scores at diagnosis (which consider age, spleen size, platelet count, and blast percentage), but the early molecular response to treatment has emerged as the most powerful predictor of long-term survival in the TKI era, as supported by the European LeukemiaNet 2020 recommendations 1.
• Regular monitoring of BCR-ABL1 levels is therefore essential for optimal management of CML patients, allowing for timely adjustments to treatment and minimizing the risk of disease progression, as highlighted in the study by Hanfstein et al 1. The rate of decline in BCR-ABL1 transcripts also correlates with longer-term response, with faster decline associated with superior outcomes, as demonstrated in the German CML IV study 1. Overall, the achievement of early molecular response to TKI therapy is the most significant predictor of survival in CML patients, and regular monitoring of BCR-ABL1 levels is crucial for optimal management.

From the FDA Drug Label

The probability of remaining progression free at 60 months was 95% for patients who were in complete cytogenetic response (CCyR) with molecular response (greater than or equal to 3 log reduction in BCR-ABL transcripts as measured by quantitative reverse transcriptase polymerase chain reaction) at 12 months, compared to 89% for patients in CCyR but without a major molecular response and 70% in patients who were not in CCyR at this time point (p less than 0.001).

The best predictor of survival in CML patients is achieving a complete cytogenetic response (CCyR) with a molecular response (greater than or equal to 3 log reduction in BCR-ABL transcripts) at 12 months. Key points include:

• CCyR with molecular response: 95% probability of remaining progression free at 60 months
• CCyR without molecular response: 89% probability of remaining progression free at 60 months
• No CCyR: 70% probability of remaining progression free at 60 months 2

From the Research

Best Predictor of Survival in CML Patients

The best predictor of survival in Chronic Myeloid Leukemia (CML) patients can be determined by assessing BCR-ABL1 transcript levels at specific time points during treatment.

• BCR-ABL1 transcript levels at 3 months have been identified as a significant predictor of overall survival (OS) and other outcomes in CML patients treated with tyrosine kinase inhibitors (TKIs) 3.
• A study found that patients with BCR-ABL1 transcript levels of more than 9.84% at 3 months had significantly lower 8-year probabilities of OS compared to those with lower transcript levels 3.
• Another study confirmed that achieving a major cytogenetic response (MCyR) within the first 2 years of treatment predicted a better OS, with a 10-year OS of 88% for patients who achieved MCyR 4.
• The BCR-ABL1 transcript level at 3 months has also been shown to predict long-term outcomes following second-generation TKI therapy in patients who failed imatinib, with better OS observed in patients achieving <1% (IS) and 1-10% (IS) compared to those with ≥ 10% (IS) at 3 months 5.
• Additionally, the decline ratio of BCR-ABL1 transcript levels combined with BCR-ABL1IS has been proposed as a precise predictor for imatinib response and outcome in CML patients, especially for those with BCR-ABL1IS >10% 6.
• A prediction model for sustained deep molecular response has also been developed, which proposes optimal values for BCR-ABL1 transcript levels at 3,6,9, and 12 months to predict the highest probability of reaching a sustained MR4.5 7.

Key Findings

• BCR-ABL1 transcript levels at 3 months are a significant predictor of OS and other outcomes in CML patients treated with TKIs.
• Achieving MCyR within the first 2 years of treatment predicts a better OS.
• The BCR-ABL1 transcript level at 3 months predicts long-term outcomes following second-generation TKI therapy in patients who failed imatinib.
• The decline ratio of BCR-ABL1 transcript levels combined with BCR-ABL1IS is a precise predictor for imatinib response and outcome in CML patients.
• A prediction model for sustained deep molecular response has been developed to predict the highest probability of reaching a sustained MR4.5.