Background <p>T-prolymphocytic leukemia (T-PLL) is a rare mature T-cell neoplasm with poor prognosis that mainly affects elderly people. Alemtuzumab is widely considered as first-line therapy, but almost all patients relapse within one year, if not consolidated by an allogeneic stem cell transplantation. The improved understanding of T-PLL-specific molecular pathomechanisms gained over the last years suggested new potential therapeutic targets (epigenetic dysregulation, defective DNA damage response, aberrant cell cycle regulation, dysregulated prosurvival pathways), which were recently evaluated in a preclinical drug response study. In addition, existing genomewide T-PLL gene expression profiles enabled the identification of three robust T-PLL gene expression subgroups differing in cellular processes like immune response, cellular respiration, cell proliferation, apoptosis, or migration. So far, these T-PLL gene expression subgroups were not considered in preclinical drug response analyses, but recently published drug response screens and corresponding already publicly available gene expression profiles offer the great opportunity to integrate both data types. Therefore, we computationally analyzed samples from 34 T-PLL patients of two comparable cohorts for their response to in total 11 drugs.</p> Results <p>No T-PLL subgroup-specific differences or sex differences in response to the tested drugs were found. With respect to the underlying drug dosage schemes, venetoclax and cladribine were most effective in erasing T-PLL cancer cells among both cohorts. Also dinaciclib, idasanutlin, romidepsin, and KRT-232, which were only tested in one of both cohorts, were very effective for all or most of the T-PLL patient samples. For the three drugs bendamustine, cladribine, and fludarabine, which were only effective in a subset of the T-PLL samples, an exploratory differential gene expression analysis predicted drug-specific genes that distinguished between strongly and not strongly responding samples. In-depth annotation and literature analyses showed that many of these genes are known to play a role in leukemias or other types of cancer. Many of these genes were also confirmed by a direct correlation analysis between gene expression levels and drug responses.</p> Conclusions <p>The absence of T-PLL gene expression subgroup-specific drug responses across the tested drugs can be important for the design of future drug screens and may ease potential clinical trials. Genes associated with drug-specific responses could be useful for improved patient stratification and may help to characterize molecular settings associated with effective responses.</p> Clinical trial number <p>Not applicable.</p>