Hematopathologic Evaluation of Myelodysplastic Features of Patients with CP-CML on Therapy with Clonal Cytogenetic Abnormalities In Ph Negative Clones

Cytogenetic clonal aberrations in CML are a well recognized indicator of transition to blast phase. However, it is unclear how to interpret such changes when they occur in cells not harboring a Philadelphia Chromosome (Ph-), considering that some of these changes are often seen in patients with MDS/AML and isolated cytopenias can also be seen in CML patients in long term therapy with TKIs.

We retrospectively reviewed 341 CML cases from January 2000 to July 2010, and determined the frequency, onset, character, and general course among CML patients harboring clonal chromosomal abnormalities (ChA) in Ph- cells during treatment with tyrosine kinase inhibitors (TKI's). In addition, we also performed a comprehensive hematopathology review on the bone marrow biopsy specimens of each case and categorized them based on findings comparable to bone marrow features found in MDS. Finally we will study the presence of TCR clonality and LGL expansions in relation with these findings.

In this review, we were able to identify 41 ChA among 36 patients (10.5% of cohort), with most cases demonstrating trisomy 8 (47% cohort) and loss/gain of chromosome Y (22% cohort). The median age was 62 years (range 33 – 78), with a male to female ratio of 7:2. The median number of treatments per patient was 2 (1-3), with a median follow-up of 77.5 months (18-196 mo). On hematopathologic evaluation of this cohort of 36 patients, only 3 patients (8% of cohort) had persistence of bone marrow features comparable to findings in MDS. Two cases demonstrated megaloblastoid erythroid features on the bone marrow, and another exhibited occasional hypogranulated granulocytes and nuclear irregularity in the erythroid precursors. Of note, 1 patient had concomitant mantle cell lymphoma at the time of diagnosis and residual MCL was found on review of several subsequent bone marrow biopsies. Post-treatment with TKIs 25 patients (69%) had normal cellularity or hypocellularity on bone marrow. The average percent cellularity on initial bone marrow post-treatment was 18.7%, reflective of the frequent cytopenias seen post-therapy. The more pronounced cytopenias were found in patients with persistent ChA. On peripheral blood evaluation the mean hemoglobin was 11.8g/dL, hematocrit 34%, and platelets 171,000/μL on presentation, with the majority of patients being transfusion independent. Of the 41 ChA, there were 2 patients who had marked hyperdiploidy with several ChA. One patient had a total of 7 different trisomies, in addition to a chromosome 17 deletion and t (7; 8). Post-therapy this patient's hyperdiploidy improved with an initial chromosomal number of 53 pre-treatment to 46 post-treatment, with the deletion 17 and t(7;8) remaining persistent throughout. The other patient, exhibiting the second highest hyperdiploid state, also had t (7; 8); interestingly, this chromosomal aberrancy emerged post-therapy, along with 1q32 and 3q12 ChA. Overall, none of these hematopathologic findings were however strongly consistent with the morphological findings typical for MDS.

In summary, while clonal cytogenetic changes in Philadelphia Chromosome positive cells are a well recognized marker of disease progression, their presence in cells lacking this translocation does not seem to reflect a similar disposition. Additionally, on closer hematopathological review, the majority of the cytopenias seen in these patients are not consistent with definitive changes consistent with MDS. In this review of 341 patients, 36 patients with Ph- ChA, none of our cases had findings sufficient for diagnosis of MDS, suggesting the ChA post-therapy with TKIs are likely a benign feature. However, long term follow-up is still needed to confirm these data. Further relations with TCR clonality and LGL expansions will be presented.

No relevant conflicts of interest to declare.