High Levels of CD34 Expression in Bone Marrow Trephines Predicts for Loss of Cytogenetic Response in Patients with in Chronic Phase Who Have Achieved Complete Cytogenetic Remission on Imatinib Therapy.

We studied the expression of CD34 in bone marrow trephines in 71 patients with CML in CP who had achieved complete cytogenetic remission (CCyR) on imatinib in order to predict the durability of the cytogenetic response. 26 patients received the imatinib shortly after diagnosis while 45 were treated after interferon failure. Imatinib was given at a dose of 400 mg daily. Imatinib dosage was adjusted depending on tolerance and response. Bone marrow examinations were performed every 3-6 months. The CD34 stain was performed in paraffin sections with the monoclonal antibody QBEND10. A minimum of 500 nucleated cells were counted per trephine section. Results were expressed as percentage of CD34+ vs all nucleated marrow cells. The expression of CD34 by the endothelial cells was used as an internal positive control. The median follow up was 1120 days (percentile 25 and 75: 960 and 1254 days). The median time to the achievement of CCyR was 254 days (percentile 25 and 75: 167 and 380 days). Eight patients lost CCyR at a median time of 981 days (range 546 to 1428 days). For the study we used the first evaluable bone marrow taken after the start of the imatinib therapy (median time 242 days; percentile 25 and 75: 110 and 342 days. The median value of CD34 was 0.9% (percentile 25 and 75 percentiles: 0.8 and 1%). Univariate and multivariate analysis for loss of CCyR was performed. The variables included in the analysis were: age, sex, Sokal and Euro risk groups, percentage of blasts in the bone marrow aspirate, new patient vs IFN intolerant, time from diagnosis to the start of the imatinib therapy and the presence of additional cytogenetic abnormalities. The only variable found to be significant in the univariate and in the multivariate analysis was the level of CD34, RR=2.45 (95CI 1.29–4.64, p=0.006). When the variable was categorised as CD34 level <=2% and CD34 level >2% the cumulative incidence of loss of CCyR at 4 years was 10.58% (95CI 3.8–10.6%) in the patients with a CD34 <=2% (n=64) vs 75% (95CI 31.9–95.1%) in the patients with a CD34 >2% (n=7), p<0.0001. BCR-ABL positive hematopoietic progenitors resistant to imatinib are detectable in all the patients who have achieved cytogenetic remission (Bhatia, 2003. Graham 2002) and may be important in disease relapse. We have shown that patients in CCyR whose percentage of CD34 positivity in trephine biopsies. taken shortly after commencing imatinib, is in excess of 2% are much more likely to lose cytogenetic remission than those with lower levels. We speculate that an increase in CD34 expression could reflect an increase in leukemic precursors in some patients.