Age and dPCR can predict relapse in CML patients who discontinued imatinib: The ISAV study

Abstract

Imatinib is effective for the treatment of chronic myeloid leukemia (CML). However even undetectable BCR-ABL1 by Q-RT-PCR does not equate to eradication of the disease. Digital-PCR (dPCR), able to detect 1 BCR-ABL1 positive cell out of 10 7 , has been recently developed. The ISAV study is a multicentre trial aimed at validating dPCR to predict relapses after imatinib discontinuation in CML patients with undetectable Q-RT-PCR. CML patients under imatinib therapy since more than 2 years and with undetectable PCR for at least 18 months were eligible. Patients were monitored by standard Q-RT-PCR for 36 months. Patients losing molecular remission (two consecutive positive Q-RT-PCR with at least 1 BCR-ABL1/ABL1 value above 0.1%) resumed imatinib. The study enrolled 112 patients, with a median follow-up of 21.6 months. Fifty-two of the 108 evaluable patients (48.1%), relapsed; 73.1% relapsed in the first 9 months but 14 late relapses were observed between 10 and 22 months. Among the 56 not-relapsed patients, 40 (37.0% of total) regained Q-RT-PCR positivity but never lost MMR. dPCR results showed a significant negative predictive value ratio of 1.115 [95% CI: 1.013-1.227]. An inverse relationship between patients age and risk of relapse was evident: 95% of patients <45 years relapsed versus 42% in the class 45 to <65 years and 33% of patients 65 years [P(v 2 ) < 0.0001]. Relapse rates ranged between 100% (<45 years, dPCR1) and 36% (>45 years, dPCR-). Imatinib can be safely discontinued in the setting of continued PCR negativity; age and dPCR results can predict relapse.

Imatinib withdrawal syndrome and longer duration of imatinib have a close association with a lower molecular relapse after treatment discontinuation: the KID study

“…This analysis was based on additional clinical observations: first, we observed an interesting phenomenon in some patients who developed musculoskeletal pain with or without pruritus after discontinuation of IM, implying a possible link to autoimmunity; 11 and second, detectable minimal residual leukemia by the more sensitive approach of dPCR may have a significant positive predictive value for molecular relapse. 9 In this study, we observed that most IM-related adverse events such as nausea, indigestion, peripheral edema, and skin whitening and fragility were rapidly resolved, whereas musculoskeletal pain and pruritus were newly developed or worsened in some patients after IM discontinuation. These observations are similar to the findings of the S.-E. Lee et al 720 haematologica | 2016; 101(6) …”

“…Increased IM therapy duration was reported to be strongly associated with a higher probability of sustained UMRD in previous studies. 1,3,6,7 Sokal risk score, 1,4,6 sex, 1 prior interferon treatment, 4,7 UMRD duration before IM discontinuation, 3,7 time to UMRD, 6 age, 9 and dPCR 9 were also reported as potential predictive factors, albeit with conflicting data. To identify additional predictors and to validate predictors explored in our previous study, 3 we performed further analysis with more patients who had at least 12 months of follow-up.…”

“…9,12 A brief method is provided in the Online Supplementary Methods. To identify the optimal cut-off S.-E. Lee et al 718 haematologica | 2016; 101(6) in the 765 chambers analyzed by dPCR for predicting loss of MMR, we performed a receiver operating characteristic curve analysis and applied different cut-off levels iteratively in steps of 1 positive chamber.…”

“…4 Currently, the ISAV and EURO-SKI studies are exploring the additional predictors of age, digital polymerase chain reaction (dPCR) results, and withdrawal syndromes such as musculoskeletal pain and pruritus. 9,10 Our previous study of health-related profiles including quality of life (HRQOL) also demonstrated that IM withdrawal syndrome can develop in some patients.…”

“…Imatinib withdrawal syndrome and longer duration of imatinib have a close association with a lower molecular relapse after treatment discontinuation: the KID study Sung-Eun Lee, 1 Soo Young Choi, 1 Hye-Young Song, 1 Soo-Hyun Kim, 1 Mi-Yeon Choi, 1 Joon Seong Park, 2 Hyeoung-Joon Kim, 3 Sung-Hyun Kim, 4 Dae Young Zang, 5 Sukjoong Oh, 6 Hawk Kim, 7 Young Rok Do, 8 Jae-Yong Kwak, 9 Jeong-A Kim, 10 Dae-Young Kim, 11 Yeung-Chul Mun, 12 Won Sik Lee,13 Myung Hee Chang, 14 Jinny Park, 15 Ji Hyun Kwon, 16 and Dong-Wook Kim…”