The patient presented here had a very poor prognosis due to previous chronic lymphocytic leukemia with unfavourable cytogenetics (deleted 17p and p53), therapy-related acute myeloid leukemia (intact 17p/p53), multiple pre-treatments (fludarabine, rituximab-CHOP, rituximab-bendamustine), advanced age (71 years) and several comorbidities—circumstances that usually do not allow high-dose chemotherapy or stem cell transplantation. Due to this unfavourable condition and reportedly poorer outcome of therapy-related acute myeloid leukemia relative to de novo acute myeloid leukemia with chemotherapy, treatment with the hypomethylating agent 5-azacitidine (Vidaza®), 75 mg/m2/day, subcutaneously for 7 days of 28-day cycles was started. Therapy was well tolerated and yielded a good response not only by eradicating the therapy-related acute myeloid leukemia but also by keeping the chronic lymphocytic leukemia under control for a rather long period of time. The simultaneous suppression and re-appearance of both the therapy-related acute myeloid leukemia with intact p53 and the chronic lymphocytic leukemia with deleted p53 suggests that hypomethylation by azacitidine attains tumour control by a mechanism that (i) is similar in the different tumours and (ii) acts independently of the p53 status. This case may serve as a model for disease progression mirrored in molecular and cytogenetic findings which are factored into treatment decisions.