The incidence of certain malignancies is significantly higher after organ transplant. However, there are rare reports of chronic myeloid leukemia in the posttransplant setting. The average reported interval between a transplant and the diagnosis of chronic myeloid leukemia is 44 months (range, 10-96 mo). We report 2 patients with chronic myeloid leukemia within 1 year of a kidney transplant, which is significantly shorter than those previously reported. Both patients were receiving mycophenolate mofetil and tacrolimus for immunosuppression. They were treated with imatinib for chronic myeloid leukemia, and both patients demonstrated an isolated elevation of serum alkaline phosphatase that was directly correlated with imatinib. Despite a potential interaction between the 2 drugs, blood levels of tacrolimus and imatinib were not elevated during the course of treatment. Isolated elevation of alkaline phosphatase in this particular setting has not been reported previously.

Key words : Renal transplant, Gleevec, CML, Immunosuppression, Imatinib

Introduction

Particular malignancies have demonstrated an increased incidence in immunosuppressed patients after an organ transplant.¹ To date, only 24 cases of chronic myeloid leukemia (CML) associated with immunosuppression have been reported^2-20; of these, 17 developed after kidney transplant.^{3-8, 10-17, 19, 20} The average reported interval between initiation of immunosuppression and detection of CML is 44 months (range, 10-96 mo). Nine patients have been successfully treated with imatinib without complications.^14-20

We report 2 patients whose CML was diagnosed within 1 year of a kidney transplant. Both experienced an isolated elevation of serum alkaline phosphatase (ALP) directly correlated with imatinib, a complication that has not been reported previously.

Case Reports

Case 1
In March, 2008, a 17-year-old boy received a kidney from a deceased donor for transplant for end-stage renal disease, secondary to IgA nephropathy and focal segmental glomerulosclerosis. The donor, a 17-year-old girl who died from streptococcal meningitis, had no significant medical history. The recipient was induced with a rabbit antithymocyte antibody and rapid steroid withdrawal protocol, and received mycophenolate mofetil and tacrolimus for maintenance immunosuppression. His baseline levels, posttransplant complete blood counts, and differentials were in the normal ranges. An elevated white blood cell count (WBC) was first detected in November 2008. A bone marrow examination in April 2009 was consistent with CML, and cytogenetic studies confirmed the presence of t(9;22)(q34;q11.2). A polymerase chain reaction test detected a p210 BCR-ABL fusion transcript level of 0.55.

In June 2009, with a WBC of 37.0 × 10⁹/L, treatment with imatinib 300 mg per day was initiated. The dosage was chosen owing to a concern of a drug interaction between imatinib and tacrolimus, both substrates of the hepatic CYP3A4 system. Within 2 weeks, a hematologic remission was achieved, results of liver function testing remained normal (with a minor elevation of ALP from 76 U/L to 113 U/L), and his creatinine was stable at baseline levels. His blood trough levels of tacrolimus remained in the desirable range (5-8 ng/mL). The dosage of imatinib was increased to 400 mg per day.

Within the next few weeks, his complete blood count, kidney functions, tacrolimus trough level, and liver function testing (including bilirubin) remained stable, but his ALP levels continued to rise. The imatinib dosage was reduced to 300 mg per day with no response in ALP; therefore, treatment was discontinued in July 2009. Later, the ALP declined to its normal level, and imatinib was restarted at 300 mg per day. But within 1 week, the patient’s creatinine increased; therefore, imatinib was held again. The creatinine level continued to rise, and a kidney biopsy diagnosed acute cellular rejection. Corticosteroid pulse therapy was given and imatinib was not reinitiated. In October 2009, the patient was admitted to the hospital for fever and cough, and died within a day. An autopsy was suggestive of H1N1 influenza infection. Figure 1 shows the ALP trend and its correlation with imatinib dosage in this patient.

Case 2
This 55-year-old man received a kidney transplant from a deceased donor in September 2008 for end-stage renal disease, secondary to diabetic nephropathy. The donor was a 50-year-old woman with no significant medical history who had died of a cerebrovascular accident. The recipient was induced with a rabbit antithymocyte antibody and rapid steroid withdrawal protocol, and received mycophenolate mofetil and tacrolimus for maintenance immunosuppression. His pretransplant and posttransplant complete blood counts and differentials were within the normal ranges. In February 2009, a mildly elevated WBC was noted that continued to increase gradually. A bone marrow examination in July 2009 was consistent with CML, and cytogenetics confirmed the presence of t(9;22)(q34;q11.2). A polymerase chain reaction test also detected a p210 BCR-ABL fusion transcript level of 0.91.

In August 2009, with a WBC of 39.0 × 10⁹/L, treatment with 300 mg per day of imatinib was initiated. The results of baseline liver function tests were normal. He achieved a hematologic remission within a few weeks, and the dosage of imatinib was increased to 400 mg per day. With treatment, his ALP gradually increased, while the results of other liver function tests remained normal. His tacrolimus trough blood level remained in the desirable range, and his creatinine remained at the baseline level. The upward trend of ALP continued; therefore, we held imatinib in September 2009. In October 2009, after an adequate decline in ALP, imatinib was restarted at 300 mg per day. A month later, while on 300 mg, a plasma imatinib level was 556 ng/mL, which is considered suboptimal.21 Within the next few months, owing to slowly increasing ALP, the dosage of imatinib was gradually reduced, which kept the ALP in range of 150-170 U/L. Subsequently, the imatinib dosage was slowly increased, and the ALP remained stable at 150-170 U/L. Results of other liver function tests, creatinine, and the tacrolimus trough blood levels remained unaffected. A recent fluorescence in situ hybridization study on peripheral blood demonstrated 30% positivity for BCR/ABL, down from 93% initially. Figure 2 shows the ALP trend and its correlation with imatinib dosage in this patient.

Both mate kidney recipients from these donors, to date, have not shown any clinical or hematologic evidence of CML and maintain normal graft function.

Discussion

Our patients add to the small number of CML cases reported in association with the postorgan transplant immunosuppressed state (Table 1). It remains controversial (owing to the limited number of reported cases) whether the incidence of CML in such patients is truly higher than the general population.^{19, 22, 23} Use of highly sensitive polymerase chain reaction technology has demonstrated intermittently detectable BCR/ABL fusion transcripts in the peripheral blood of up to 30% of normal healthy adults.²⁴ Speculation of such clones not being removed or spontaneously recovered under the immunosuppressed conditions is intriguing.

le Coutre and associates detected BCR/ABL rearrangement in the peripheral blood of 5 cases among 100 randomly selected postorgan transplant patients with no hematologic findings suggestive of CML.¹⁹ This finding carried a statistically significant difference (P = .02) compared with controls. However, both patients in this cohort from whom follow-up samples were available tested negative for BCR/ABL 1 year later. This indicates the preserved ability, under the immunosuppressed conditions, of converting the BCR/ABL positive status to negative.

Among previously reported patients (excluding the 1 patient who likely had CML before transplant),¹⁰ the average interval between the initiation of immunosuppression and the diagnosis of CML was 44 months (range, 10-96 mo). An interval of less than 1 year has been reported in only 1 patient with 1 transplant history.¹⁹ Interestingly, the CML was detected within 1 year in both of our cases. Neither of the donors had a history suspicious for leukemia, and both the mate kidney recipients from these donors have maintained a normal WBC with no evidence of leukemia. This excludes the remote possibility of CML transmitted by the transplanted organ. The average interval was 34 months (range, 10-72 mo) in the 10 reported patients who, similar to our cases, were taking mycophenolate mofetil and/or tacrolimus for immunosuppression. The shorter interval seen in recent cases can be attributed to more-sensitive detection techniques for the BCR/ABL. This observation also may represent the possibility of faster emergence of malignant clones when using newer immunosuppressants.

Both our patients demonstrated an isolated elevation of serum ALP in direct correlation with the use of imatinib. Elevation of liver enzymes is seen occasionally with imatinib, but an isolated increase in ALP is uncommon. It is possible that if these patients had not been followed closely with the imatinib dosage adjusted, other liver enzymes also would have increased later. The development of this uncommon adverse effect in 2 consecutive patients on same type of immunosuppressive agents raises the question of drug interaction.

Imatinib and tacrolimus are both metabolized via the hepatic CYP3A4 system. We monitored tacrolimus trough blood levels in both patients and did not notice any changes. Also, measurement of the plasma imatinib level in our second patient showed subtherapeutic values. Thus, the isolated increase in ALP cannot be attributed to elevation of the drug blood levels owing to an interaction between the 2 agents. In addition, we cannot point to a potential interaction between imatinib and mycophenolate mofetil because they are metabolized via different pathways.

Nine other patients in the literature have been treated with imatinib for postorgan transplant CML.^14-20 Six of them received mycophenolate mofetil and/or tacrolimus for immunosuppression, but there is no report of liver dysfunction or ALP abnormalities. Therefore, our patients represent the only reported cases with such a complication in the setting of postorgan transplant immunosuppression.

We reported 2 consecutive cases of postkidney transplant CML. Both patients were receiving mycophenolate mofetil and tacrolimus for immunosuppression and developed CML within 1 year of their transplant. They were treated with imatinib and obtained a response, but both developed an isolated elevation of serum ALP that was directly correlated with imatinib.

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