ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition

ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in three infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALKrearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (seven and twelve from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated-ERK, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, while CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, ten with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis, and provides guidance for the clinical management of this emerging histiocytic entity.Molecular tumour pathology - and tumour genetic

Transport phenomena of carbazole biodegradation by immobilized thalasosspira profundimaris cell and mechanical properties

Carbazole is a heterocyclic aromatic compound that imposes threat to the environment when contaminates water source. A marine-isolated bacterium, Thalassospira profundimaris shows ability to degrade carbazole. The use of free-cell for bioremediation is inefficient as the cells are exposed to harsh environmental condition. In this study, immobilizations of T. profundimaris in gellan gum were investigated to develop robust systems for bioremediation. The mechanical strength and its relationship with transport of carbazole was investigated. The findings proved that concentration of immobilization media affects diffusivity and mechanical strength. Higher media concentration formed a stronger bead with lower diffusivity where lower concentration formed soft bead with higher diffusivity. The optimum concentration of gellan gum was 0.7% (w/v) with 61% carbazole degradation recorded and an optimum diffusivity of 36.8 × 10-7 cm2/s. It has the highest Young's modulus (0.041810 N/mm2) among other concentrations. The findings of the optimum carbazole degradation, strength and diffusivity were profound to increase the performance of the bacteria entrapped inside the immobilization media for bioremediation and withstand harsh environment

Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms

Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis

Non-Relapse Mortality in TP53 -Mutated MDS/AML - a Multi-Center Collaborative Study

Abstract Background: Patients with TP53 MUT MDS/AML experience poor clinical outcomes with high rates of disease recurrence and short overall survival (OS). Characterization of these individuals' post-HCT mortality is uniquely challenging due to competing risks from disease relapse and treatment toxicity. Transplant registries contain high-level outcomes data, however, there is a lack of detailed data in molecularly defined subsets of diease. This analysis was undertaken to bridge this gap. Methods: Allogeneic HCT recipients between 1/2014 and 12/2018 were retrospectively studied. Key inclusion criteria were TP53 MUT by NGS or deletion of chromosome 17/17p by FISH/cytogenetics. The primary outcome of non-relapse mortality (NRM) was defined as death from any cause other than disease with relapse as competing risk. Secondary outcomes for this analysis were OS, cumulative incidence of relapse (CIR), and relapse free survival (RFS). Relapse was defined as relapse/progression with NRM as competing risk. Results: 384 TP53 MUT MDS/AML patients were analyzed. 55% of patients were transplanted for AML, 41% received myeloablative conditioning (MAC), 39% had secondary MDS/AML, and 26% received prior chemo and/or radiation therapy (XRT). Median time from HCT to last follow-up was 321 days (range 8-2,385 days). Mutational data was available in 264 patients and cytogenetic data was available in 368 patients; 78% of patients had a complex karyotype (CK), 82% had TP53 missense mutations, and 74% had bi-allelic targeting of the TP53 gene. The incidence of all-grade acute and chronic GVHD (cGVHD) was 52% and 31%, respectively. One and 2 year OS was 48.5% and 30.9%, respectively. Estimated CIR at 1 and 2 years was 49% and 54.9%, respectively. The 1 year NRM was 13.7% and 2 year NRM was 18.1%. In multivariate analysis (MVA), there was no association between NRM and the clinical, molecular, or genetic features of TP53 MUT MDS/AML. HCT diagnosis of MDS (HR: 0.67, 95% CI: 0.46-0.97, p: 0.036), mono-allelic TP53 MUT (HR: 0.6, 95% CI: 0.39-0.94, p: 0.023), achievement of full donor PB chimerism (HR: 0.33, 95% CI: 0.14-0.85, p: 0.022), BM chimerism (HR: 0.33, 95% CI: 0.18-0.60, p: 0.003), and cGVHD (HR: 0.35, 95% CI: 0.23-0.51, p: <0.001) correlated with lower rates of relapse while CK predicted for increased relapse (HR: 2.5, 95% CI: 1.49-4.19, p: 0.001). Inferior OS was associated with CK (HR: 1.84, 95% CI: 1.19-2.85, p: 0.006) and history of prior chemo/XRT (HR: 1.84, 95% CI: 1.01-1.93, p: 0.006) whereas high KPS (HR: 0.98, 95% CI: 0.97-1, p: 0.046), mono-allelic TP53 mutations (HR: 0.52, HR: 0.36-0.77, p: 0.001), full donor PB chimerism (HR: 0.36, 95% CI: 0.19-0.68, p: 0.002), BM chimerism (HR: 0.3, 95% CI: 0.19-0.49, p: <0.001), and cGVHD (HR: 0.36, 95% CI: 0.18-0.36, p: <0.001) were associated with improved OS. In subgroup analysis, history of chemo and/or XRT increased NRM in AML (HR: 4.24, 95% CI: 1.35-13.39, p: 0.014). Pre-HCT TP53 MUT persistence by NGS (HR: 3.59, 95% CI: 1.43-9, p: 0.007) predicted for post-HCT relapse whereas pre-HCT CR (HR: 2.93, 95% CI: 1.54-5.59, p: 0.001) and full donor BM chimerism (HR: 0.14, 95% CI: 0.05-0.38, p: <0.001) were associated with lower rates of relapse. High KPS (HR: 0.96, 95% CI: 0.98-0.99, p: 0.021) and cGVHD (HR: 0.3, 95% CI: 0.16-0.56, p: <0.001) corresponded with improved OS. Prior chemo/XRT was associated with shorter OS (HR: 2.11, 95% CI: 1.06-4.18, p: 0.033) No significant NRM associations were identified in MDS. CK (HR: 5.04, 95% CI: 1.95-13.01, p: <0.001) and RIC/NMA conditioning intensity (HR: 2.54, 95% CI: 1.26-5.1, p: 0.009) increased risk of post-HCT relapse while full donor BM chimerism (HR: 0.15 95% CI: 0.08-0.31, p: <0.001), full donor PB chimerism (HR: 0.17, 95% CI: 0.17, p: <0.001), and cGVHD (HR: 0.17, 95% CI: 0.07-0.42, p:<0.001) reduced this risk. OS was improved with mono-allelic mutations (HR: 0.54, 95% CI: 0.32-0.96, p: 0.034), full donor BM (HR: 0.24, 95% CI: 0.12-0.71, p: <0.001), PB (HR: 0.29, 95% CI: 0.09-0.3, p: 0.007) chimerism, and cGVHD (HR: 0.16, 95% CI: 0.09-0.3, p: <0.001). Conclusions: From this large multi-institutional cohort of TP53 MUT myeloid neoplasms, we report a low NRM rate, likely due to high rates of post-HCT relapse/progression. These data demonstrate associations between bi-allelic TP53m/CK and post-HCT outcomes. Our work highlights the importance donor chimerism after HCT and provides new understanding of the importance of chronic GVHD in TP53 MUT MDS/AML. Figure 1 Figure 1. Disclosures Byrne: Karyopharm: Research Funding. Logan: Amgen, Pfizer, AbbVie: Consultancy; Pharmacyclics, Astellas, Jazz, Kite, Kadmon, Autolus, Amphivena: Research Funding. Lee: CareDx: Membership on an entity's Board of Directors or advisory committees; Kadmon: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Fresensius Kabi: Consultancy; Jazz,: Consultancy; Incyte: Research Funding. Goodman: Seattle Genetics: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria. Gill: Interius Biotherapeutics: Current holder of stock options in a privately-held company, Research Funding; Novartis: Other: licensed intellectual property, Research Funding; Carisma Therapeutics: Current holder of stock options in a privately-held company, Research Funding. Jimenez: Takeda: Research Funding; AbbVie: Research Funding. Metheny: Pharmacosmos: Honoraria; Incyte: Speakers Bureau. Bhatnagar: Pfizer: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Cell Therapeutics: Honoraria, Research Funding; Kite: Honoraria; Karyopharm: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Research Funding. Hamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees. Mishra: Novartis: Research Funding. Savona: BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding