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Deep molecular response predicts outcome of CML

NEW YORK (Reuters Health) – A deep molecular response predicts long-term outcomes in patients with chronic myeloid leukemia (CML), researchers from Germany report.

A deep molecular response, defined as at least a 4.5 log reduction of residual BCR-ABL transcripts (MR4.5), “is a pre-stage of cure” and should be achieved before attempting to discontinue therapy with tyrosine kinase inhibitors, Dr. Rudiger Hehlmann from Universitaet Heidelberg in Mannheim, Germany told Reuters Health.

“MR4.5 is reached faster with tolerability adapted high-dose imatinib (imatinib 800 mg per day) and in patients with early major molecular remission,” Dr. Hehlmann said in an email.

In the randomized CML-Study IV, Dr. Hehlmann and colleagues evaluated the proportion of patients achieving MR4.5, analyzed whether MR4.5 is reached faster with optimized high-dose imatinib, and investigated whether the achievement of MR4.5 improved survival over that with less deep remissions.

Among 1,551 patients with newly diagnosed chronic phase CML and a median follow-up of 67.5 months, the five-year survival was 90.0%, the five-year progression-free survival (PFS) was 87.5%, and the eight-year overall survival probability was 86%, according to a report online December 2 in the Journal of Clinical Oncology.

As Dr. Hehlmann pointed out in his email, patients with optimized high-dose (800 mg/day) imatinib achieved MR4.5 more quickly (48 months) than patients on low-dose (400 mg/day) imatinib (62 months).

The cumulative incidence of MR4.5 reached 66% after eight years and 70% after nine years, with a median time to MR4.5 over all treatments of 4.9 years.

MR4.5 at four years was associated with a significantly higher overall survival probability (92%) than CCR (83%; p=0.047), but this did not differ significantly from major molecular remission (MMR) or MR4.

No patient with MR4.5 experienced progression after a median observation time of three years, whereas 13 patients have progressed after CCR after median observation times ranging from 3.8 to 4.7 years.

Early MMR predicted MR4.5, as did EUTOS low-risk, age younger than 65 years, and imatinib 800 mg/day versus other regimens.

“MR4.5 is the first molecular marker shown to be more predictive of long-term survival than is CCR,” the researchers note. “This observation lends support to the concept that tyrosine kinase inhibitors can cure CML if treatment is long enough and sufficiently low response levels are reached.”

“Very deep remissions can be achieved with imatinib in the majority of CML patients (70% after nine years),” Dr. Hehlmann said. “This is important, since a) imatinib is a safe drug with no serious adverse attempts after now 15 years, and b) deep molecular response is a precondition for treatment discontinuation.”

In an effort to achieve MR4.5, treatment should be continued “indefinitely for the time being,” Dr. Hehlmann said. “Switching to other treatments should follow the recently updated failure definitions of the European LeukemiaNet (ELN).”

Senior author Dr. Andreas Hochhaus from Universitaetsklinikum Jena in Jena, Germany added, also by email: “Most important in the story is the accurate and standardized measure of MR4.5, which is currently not available in general practice in the USA.”

In an editorial, Dr. Julieta Politi and Dr. Neil P. Shah from the University of California, San Francisco write, “This is the first study to our knowledge to demonstrate that achievement of a deep molecular response predicts statistically significant superior survival relative to that in patients with only a 2-log reduction in BCR-ABL transcript level (i.e., MR2), which has been suggested to be the minimal molecular response equivalent of a complete cytogenetic response.”

“Growing evidence supports the importance of achieving early and deep molecular responses in realizing longer-term outcomes,” the editorial concludes. “Provided that tolerability-adapted imatinib dosing is feasible for the majority of patients and reasonably inexpensive after imatinib patent expiration, this treatment strategy may represent an attractive option in countries where health care costs pose a substantial challenge.”

Dr. Jorge Cortes from The University of Texas MD Anderson Cancer Center in Houston has also published on deeper molecular responses in patients with CML. He told Reuters Health by email, “I believe it is adequate to try to achieve the deepest possible response in a given patient. However, as shown in this study, there is no significant survival benefit between MR4.5 and, for example, MR4 or MMR. Thus, not achieving this response should not be considered failure.”

“Adequate monitoring of patients is important to optimize outcome,” Dr. Cortes said. “Unfortunately, monitoring is not done in many patients according to the current recommendations.”

“Adequate management of a patient with CML is more than just giving them one of the excellent medications we have available for this disease,” Dr. Cortes added. “Optimal management includes also adequate identification and management of adverse events, proper monitoring, and focus on long-term goals.”


J Clin Oncol 2013.