Interferon May Help Control the Recurrence of Chronic Myeloid Leukemia after Discontinuation of Tyrosine Kinase Inhibitor

Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukemia (CML).Many patients have deep molecular responses(DMR), a prerequisite for TKIs therapy discontinuation. Many clinical studies have been done in discontinuation of TKIs worldwide. We aimed to explore the appropriate criteria for failure of TKIs discontinuation; and to observe the effect of interferon on patients with continuous low level positive BCR-ABL1 after TKIs discontinuation.

Therefore, we analyzed the clinical data of 40 CML patients with DMR who have withdrawn TKIs from Match 2013 to January 2018. Eligible CML patients had received any TKI for at least 3 years, and had a confirmed deep molecular response for at least 2 year. The molecular relapse(MR) was defined as loss of major molecular response (MMR; BCR-ABL1 >0.1% on the International Scale). The patients with MR would be prescribed TKI, and patients with 0.0032% < BCR-ABL1^IS <0.1% would be suggested to try interferon.

Of these 40 patients, male/female was 24/16, the median age was 50 (13,70) years, and 2 cases were accelerated phase, while the rest were chronic phase at diagnosis. It was feasible for Sokal score in 35 cases, including 18 cases with low risk, 12 with intermediate risk and 2 with high risk. The median time to MR4.5 was 18 (6,82) months, and the median duration of MR4.5 before TKIs discontinuation was 52 (27,115) months. Thirty-two patients had been taking imatinib and eight had been taking second-generation TKIs. The median duration of TKIs was 83.7 (37.5, 125.4) months. After drug withdrawal, median follow-up was 17.6 (6,65) months. 17 patients eventually lost MMR.TFR was 65% (95%CI (47.6%, 82.4%) at 12 months. A total of 14 patients restarted TKI treatment, 1 lost the visit, and 13 patients regained MMR or MR4.5 within 3 months after taking the medicine. There were 23 patients without losing MMR, 10 of whom maintained CMR. There were 5 cases with single positive BCR-ABL1 that did not lose MR4.Eight cases were positive for BCR-ABL1 more than twice, of which four lost MR4 (3 received interferon treatment) and four did not lose MR4 (1 received interferon treatment).

Of the 21 patients with BCR-ABL1 positive for more than 2 times after discontinuation (4 patients were excluded for loss of MMR in first positive test), 6 patients by follow-up did not lose the MR4, in 15 cases losing MR4, 12 cases eventually lose the MMR, 3 cases of follow-up did not lose the MMR (2 cases received interferon treatment), TFR for two groups was statistically difference (P = 0.026).In these 21 patients, 3 cases were non continuous positive, 18 cases of low level 2 consecutive positive, the median follow-up of 15.75 (6,55.5) months, 7 cases received interferon therapy, median follow-up after application of interferon was 9 (3, 20) months, in which 2 cases eventually lose the MMR, 11 cases treated without interferon, 10 cases eventually lose the MMR, TFR was statistically different between the two groups (71.4% vs 9.1%, P < 0.001).Among them, 2 female patients lost MMR 4 months after drug withdrawal, and because of pregnancy they did not take TKI again, they were given interferon treatment, and obtained and maintained MMR 2 months after interferon treatment. Patients with interferon are well tolerated.

After the discontinuation of TKI in CML patients, early intervention should be conducted if MR4 is lost, and interferon treatment may help maintain MMR and prolong the survival without TKI treatment.