Multicenter analysis of immunosuppressive medications on the risk of malignancy following adult solid organ transplantation.

Objective: This study aimed to assess the risk of maintenance immunosuppression on the post-transplant risk of malignancy across all solid organ transplant types. Methods: This is a retrospective cohort study from a multicenter hospital system in the United States. The electronic health record was queried from 2000 to 2021 for cases of solid organ transplant, immunosuppressive medications, and post-transplant malignancy. Results: A total of 5,591 patients, 6,142 transplanted organs, and 517 post-transplant malignancies were identified. Skin cancer was the most common type of malignancy at 52.8%, whereas liver cancer was the first malignancy to present at a median time of 351 days post-transplant. Heart and lung transplant recipients had the highest rate of malignancy, but this finding was not significant upon adjusting for immunosuppressive medications (heart HR 0.96, 95% CI 0.72 - 1.3, p = 0.88; lung HR 1.01, 95% CI 0.77 - 1.33, p = 0.94). Random forest variable importance calculations and time-dependent multivariate cox proportional hazard analysis identified an increased risk of cancer in patients receiving immunosuppressive therapy with sirolimus (HR 1.41, 95% CI 1.05 - 1.9, p = 0.04), azathioprine (HR 2.1, 95% CI 1.58 - 2.79, p < 0.001), and cyclosporine (HR 1.59, 95% CI 1.17 - 2.17, p = 0.007), while tacrolimus (HR 0.59, 95% CI 0.44 - 0.81, p < 0.001) was associated with low rates of post-transplant neoplasia. Conclusion: Our results show varying risks of immunosuppressive medications associated with the development of post-transplant malignancy, demonstrating the importance of cancer detection and surveillance strategies in solid organ transplant recipients.

Application of Next-Generation Sequencing-Based Mutational Profiling in Acute Lymphoblastic Leukemia.

PURPOSE OF REVIEW: Recent efforts to characterize hematologic cancers with genetic and molecular detail have largely relied on mutational profiling via next-generation sequencing (NGS). The application of NGS-guided disease prognostication and clinical decision making requires a basic understanding of sequencing advantages, pitfalls, and areas where clinical care might be enhanced by the knowledge generated. This article identifies avenues within the landscape of adult acute lymphoblastic leukemia (ALL) where mutational data hold the opportunity to enhance understanding of disease biology and patient care. RECENT FINDINGS: NGS-based assessment of measurable residual disease (MRD) after ALL treatment allows for a sensitive and specific molecular survey that is at least comparable, if not superior, to existing techniques. Mutational assessment by NGS has unraveled complex signaling networks that drive pathogenesis of T-cell ALL. Sequencing of patients with familial clustering of ALL has also identified novel germline mutations whose inheritance predisposes to disease development in successive generations. While NGS-based assessment of hematopoietic malignancies often provides actionable information to clinicians, patients with acute lymphoblastic leukemia are left underserved due to a lack of disease classification and prognostication schema that integrate molecular data. Ongoing research is positioned to enrich the molecular toolbox available to clinicians caring for adult ALL patients and deliver new insights to guide therapeutic selection, monitor clinical response, and detect relapse.

Targeted Therapies for the Evolving Molecular Landscape of Acute Myeloid Leukemia.

Despite considerable growth in our understanding of the heterogeneous biology and pathogenesis of acute myeloid leukemia (AML) in recent decades, for nearly forty years, little progress was gained in the realm of novel therapeutics. Since 2017, however, nine agents have been FDA-approved for patients with AML in both the upfront and relapsed/refractory (R/R) settings. Most of these compounds function as inhibitors of key cell cycle enzymatic pathways or mediators of leukemic proliferation and survival. They have been approved both as single agents and in combination with conventional or reduced-intensity conventional chemotherapeutics. In this article, we review the molecular landscape of de novo vs. R/R AML and highlight the potential translational impact of defined molecular disease subsets. We also highlight several recent agents that have entered the therapeutic armamentarium and where they fit in the AML treatment landscape, with a focus on FLT3 inhibitors, IDH1 and IDH2 inhibitors, and venetoclax. Finally, we close with a survey of two promising novel agents under investigation that are poised to enter the mainstream clinical arena in the near future.