乌鸦传媒

HOUSTON -- An early molecular or cytogenetic response correlated with better long-term survival in heavily pretreated chronic-phase chronic myeloid leukemia (CML) treated with the BCR-ABL inhibitor ponatinib (Iclusig), a post-hoc analysis of a prospective clinical trial showed.

Patients who achieved a major molecular response (MMR; BCR-ABL1 ≤0.1%) within 3 months had a 4-year progression-free survival (PFS) rate of about 80%, whereas those who did not meet that landmark response had a 4-year PFS rate of 60% or less. The overall survival (OS) rate at 4 years was about 90% for early responders, which was numerically higher than for patients who had higher levels of BCR-ABL1.

Major or complete cytogenetic response (MCyR or CCyR) at 3 months also correlated with improved OS, said Hagop Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, during the Society of Hematologic Oncology annual meeting.

"This analysis of the PACE trial does show that in the salvage setting, the achievement of an early molecular response does correlate with long-term outcome," said Kantarjian. "What I did not show in detail is that achievement of a cytogenetic or molecular response within 12 months also correlates with improved outcomes in these patients."

In the phase II PACE trial, patients with heavily pretreated CML achieved major cytogenetic and molecular response rates as high as 70% at 12 months. Previous studies have shown that early landmark response to BCR-ABL tyrosine kinase inhibitors is associated with improved long-term outcomes in newly diagnosed CML, but limited data exist to show that the same association holds true in the salvage setting, said Kantarjian.

To examine the impact of early response in the salvage setting, investigators analyzed PACE data to explore associations between response status at 3 months and long-term outcomes, including PFS, OS, and achievement of complete response (MR4.5). The trial enrolled patients with chronic-phase CML that was resistant to dasatinib or nilotinib (Tasigna) or associated with T315I mutation.

The analysis included 233 patients, 33 of whom had an MMR within 3 months. Patients who achieved an early MMR more often had greater baseline BCR-ABL1 staining (1-10%) and T315I mutation, the reverse of what might have been expected, Kantarjian noted.

In addition to the patients who achieved MMR status at 3 months, 49% of patients had an MR1 response and 34% had MR2 responses. Reflecting deepening of responses over time, all three response categories improved, and at 12 months, 39% of patients had achieved MMR, 55% met MR2 response criteria, and 61% had MR1 responses.

Patients who achieved MMR at 3 months had significantly better 4-year PFS (P=0.0010) versus all others and had a numerically higher probability of 4-year OS, said Kantarjian. Additionally, patients who achieved an MMR by 3 months were significantly more likely to achieve deeper responses (MR4.5) at any time during follow-up (P<0.0001)

Investigators also analyzed the data according to older cytogenetic response criteria (MCyR, CCyR). Patients who met MCyR or CCyR response criteria at 3 months had significantly better PFS at 4 years (P<0.0001, P=0.0004). Additionally, MCyR and CCyR responses at 3 months were associated with significantly better 4-year OS as compared with patients who did not achieve a cytogenetic response (P=0.0006, P=0.0117).

One implication of the findings is that patients who achieve an MMR at 3 months might be considered for dose reduction, said Kantarjian. Patients who achieve an MR4.5 at 3 months are likely to have a deep molecular response and might be considered candidates for treatment-free remission.

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