Both Higher Level of (bcr,abl) Transcripts and High Hasford Risk Score Are Associated with Cytogenetic Response but Absence of Molecular Remission during First Line Use of Imatinib Mesilate(IM): A Finding Not Observed Following Use among Interferon Failures.
Authors: Toprak Selami K. , Dalva Klara , Mizrak Dilsa , Arat Mutlu , Ozcan Muhit , Gurman Gunhan , Ilhan Osman , Beksac Meral 
Published: April 2020

Factors that predict response to treatment in CML has been defined for busulphan and Interferon. Search for prognostic parameters in the imatinib era are still continuing. Very recently a new prognostic scoring of CML patients has been defined by Kantarjian et al (Blood, 2004; 10: 1182).The value of these scoring systems in prediction of molecular response to first line use of IM has not been published yet. With this aim, we have evaluated the hematological and molecular response of all CML patients chronic (n: 74)/accelerated (n: 9) treated with IM in this prospective study. Since IM has been approved for secondary ( May 2001)and primary (May 2003) treatment in Turkey, we have evaluated 22 patients- first line use (Group 1) and 61 Interferon failures (Group 2) following a median follow-up of 9–35 months. Hasford prognostic score was available and calculated in 67 of these patients online at www.pharmacoepi.de/cmlscore.html. Scores were: Group 1 low:8 /medium:5 /high:2; Group 2:low:16 /medium:29 /high:7. In group 2, time from diagnosis to IM treatment was 29 m(3–144).

Method: RNA was isolated from blood or marrow (High Pure RNA isolation kit, Roche) and used for quantitative detection of bcr-abl transcripts with “LightCycler t(9;22) Quantification Kit”. Results were expressed as ratio to G6PD standarts.

Results: Age and Hasford distribution were comparable in group 1 and 2. The tumor burden (median)according to scoring was Group1: low: 0.014 /high: 0.0453 and Group 2: low: 0.0035 /high: 0.012. Level of bcr-abl transcripts were higher in group1 vs 2(0.03 vs 0.009) and Hasford-high vs low, regardless of previous treatment. We could not show any correlation between Hasford score and transcript level at diagnosis (Pearson, r=.314, p=0.255). 20% of the Group 1-high and 60% of Group 1-low patients achieved major and complete CR at 6m and 12m. Similar evaluation revealed a weaker response rate in Group-2: 21–30% depending on risk score and time (6–12m). Time to mol CR (less than 10e5) occurred at a median of 6 (6–12) months in 26.7% (6m) of Group1 and 9m (3–12) in 7.7% (6m) of Group 2. Resistance developed both in Group 1(2/22) and Group 2 (7/61). Among scored patients, mol CR was achievable in Group-1(only low risk). However in Group 2, molCR could be obtained both in low (n:17) and high (n:17) risk patients. The median levels of bcr,abl transcript were: Group1:0.029 (molCR+) vs 0.059(molCR-) and Group 2: 0.0498 (molCR+) vs 0.0988(molCR−).

Conclusion: In accordance with previous reports both molecular and cytogenetic remissions were observed earlier and more frequently among patients who received IM as a first line agent compared to second line use. Among patients being treated after Interferon, Hasford scoring at diagnosis did not have an impact on the prediction of response to IM. This finding is in paralel to Kantarjian’s results. However, in our study de novo CML patients’ bcr,abl transcript levels and the Hasford score showed an association with response. The shorter median follow-up in Group 1 may also have an impact on these results and updates are warranted. Like ours, the recent publications (Brummendorf 2003 and Drummond, 2004) on the correlation of telomere length with Hasford score and the response to treatment with IM support the value of this score in previously untreated patients with CML.