Presence of Bcr-Abl Positive Cells in Peripheral Blood Leukocytes of Immunosuppressed Solid Organ Transplant (SOT) Recipients
Authors: le Coutre Philipp D. , Reinke Petra , Neuhaus Ruth , Trappe Ralf , Ringel Frauke , Hemmati Philipp , Dörken Bernd , Daniel Peter 
Published: April 2020

Abstract
In chronic myeloid leukemia (CML) the p210 BCR-ABL protein, generated by a t(9;22)(q34;q11) translocation, is the underlying mechanism of leukemogenesis. Although the presence of p210 BCR-ABL is normally restricted to CML patients (pts), previous reports demonstrated low levels of bcr-abl transcripts in healthy individuals that may be controlled by an intact immune system (Bose et al. Blood92:3362, 1998). Interestingly, several articles reported cases of CML occurring in pts after SOT (Pelloso et al. Leukemia Res29:353, 2005). Therefore, immunosuppressed SOT recipients should represent an optimal population to investigate the frequency of bcr-abl transcripts in non-leukemic individuals in order to address a potential impact of immunosuppression on the presence of bcr-abl transcripts. This possibility was investigated by studying peripheral blood leukocytes for the presence of bcr-abl transcripts in a total of 201 individuals of whom 100 were SOT recipients (n=50 kidney, n=46 liver, n=3 heart, n=1 heart-lung) and 101 were control individuals (n=87 patients with renal failure, n=14 healthy individuals). The male to female ratio in the study group was 54:46 (median age: 55.38 years, range: 22–83) and matched the control group (median age: 59.8 years, range: 32–96). Included in the study group were 13 pts with post transplant malignancies who were previously treated with standard chemotherapeutic regimens. Immune suppressive drugs given to all SOT recipients included steroids (90%), cyclosporine A (69%), azathioprine (22%), tacrolimus (69%), sirolimus (44%), mycophenolic acid (63%) and others (37%). For the detection of the bcr-abl transcript we used a nested reverse transcriptase-polymerase chain reaction (RT-PCR) assay that is routinely used in our institution. All samples were tested at least twice. In 5/100 immunosuppressed pts at least 1 of 2 RT-PCR products was bcr-abl positive in the second round amplification. This rate significantly exceeded the control group that was completely bcr-abl negative (0/101 p = 0.0242). Of the 5 bcr-abl positive pts, 3 were liver transplant and 2 were kidney transplant recipients. The latency in this group (interval between transplantation and bcr-abl PCR) was at 58.4 months (range: 24-135 months) and shorter when compared to the latency in the remaining study group (104.8 months; range 1 – 369). Additionally, all samples were tested for both the pml-rara and aml1-eto transcripts that are detectable in subsets of pts with acute myeloid leukaemia but none of the samples tested positive for these transcripts. Our findings are extended by three case reports of SOT recipients (2 kidney, 1 liver) who developed CML in a total of 2088 transplantations in our centre in 9 years. In these three pts (2 males, 1 female), CML occurred at 84.3 months (range: 32–183) following SOT. In summary our data show: 1. The presence of bcr-abl transcripts in immunosuppressed non-leukemic SOT pts and the absence of bcr-abl transcripts in healthy normals when tested with routine PCR protocols. 2. The absence of pml-rara and aml1-eto transcripts in both the study and control group. And 3. the occurrence of CML in three patients following SOT suggesting a higher frequency of CML in this population.