Mivavotinib (TAK-659) is an investigational type 1 tyrosine kinase inhibitor with dual activity against spleen tyrosine kinase (SYK) and FMS-like tyrosine kinase 3 (FLT3). We conducted a phase Ib study to investigate the safety, tolerability, and efficacy of mivavotinib in patients with refractory and/or relapsed (R/R) acute myeloid leukemia (AML). Both daily (QD) and twice daily (BID) dosing regimens were evaluated. A total of 43 patients were enrolled, and there were 5 complete responses (4 with incomplete count recovery). In the QD dosing regimen, the maximum tolerated dose (MTD) was not reached up to 160 mg QD per protocol; 140 mg QD was identified as the recommended phase II dose. In the BID dosing regimen, the MTD was 60 mg BID. Thirty patients (70%) experienced a bleeding event on study; the majority were grades 1 or 2, were resolved without mivavotinib modification, and were not considered related to study treatment. Eleven patients (26%) experienced grade ≥3 bleeding events, which were observed most frequently with the 80 mg BID dose. We conducted platelet aggregation studies to investigate the potential role of mivavotinib-mediated SYK inhibition on platelet function. The bleeding events observed may have been the result of several confounding factors, including AML disease status, associated thrombocytopenia, and high doses of mivavotinib. Overall, these findings indicate that the activity of mivavotinib in R/R AML is modest. Furthermore, any future clinical investigation of this agent should be undertaken with caution, particularly in thrombocytopenic patients, due to the potential bleeding risk of SYK inhibition. ClinicalTrials.gov: NCT02323113.

Primary pancreatic lymphoma (PPL) is an extremely rare type of non-Hodgkin's lymphoma (NHL). It accounts for 0.1% of all lymphomas and less than 1% of pancreatic tumors. Within this subtype, T-cell lymphomas only account for up to 6.7% of pancreatic lymphomas. In this study, we present the case of a 78-year-old Hispanic man who presented with obstructive jaundice associated with a mass within the head of the pancreas; pathologic analysis of the tumor revealed a mature T-cell lymphoma, not otherwise specified (NOS).

Introduction:Diabetes is the leading cause of end-stage renal disease (ESRD) in the United States (US), with 37 million having chronic kidney disease. Despite national guidelines recommendations for diabetic nephropathy screening with urine albumin-to-creatinine ratio (UACR), less than 50% receive full screening.Our Internal Medicine residents led a quality improvement project to increase diabetic nephropathy screening rate with UACR in our resident clinic by 50% in one academic year. Methods:We conducted the resident-led quality improvement project from July 2021 to April 2022. We reviewed the electronic medical records (EMR) from our clinic pre-intervention July 2020 to June 2021 and compared this to post intervention July 2021 to March 2022 determining the nephropathy screening rates in patients with diabetes. Our interventions included resident education, pre and post surveys to test foundational knowledge, adding UACR in the affordable laboratory order form and establishing normal reference range of UACR in the EMR. Results:We collected 217 patients with diabetes, 27% were uninsured, 38% had Medicare/Medicaid and 90% identified as Hispanic. Comparing pre to post intervention, there was a significant change of 45 (20.7%) vs 71 (32.7%) patients screened for diabetic nephropathy with a UACR. The correct average score of knowledge-based questions was 82% on the pre survey, which increased to 88% in the post survey. Conclusion:Our study showed promising results on improving diabetic nephropathy screening. The comprehensive approach including resident education about diabetic nephropathy screening with UACR and more so facilitating the order set in the EMR were key to achieve this goal.

Innate lymphoid cells (ILCs) emerge in the last few years as important regulators of immune responses and biological processes. Although ILCs are mainly known as tissue-resident cells, their precise localization and interactions with the microenvironment are still unclear. Here we combine a multiplexed immunofluorescence technique and a customized computational, open-source analysis pipeline to unambiguously identify CD127 + ILCs in situ and characterize these cells and their microenvironments. Moreover, we reveal the transcription factor IRF4 as a marker for tonsillar ILC3, and identify conserved stromal landmarks characteristic for ILC localization. We also show that CD127 + ILCs share tissue niches with plasma cells in the tonsil. Our works thus provide a platform for multiparametric histological analysis of ILCs to improve our understanding of ILC biology.

Acute myeloid leukemia patients with FLT3-ITD mutations have a high risk of relapse and death. FLT3 tyrosine kinase inhibitors improve overall survival, but their efficacy is limited and most patients who relapse will ultimately die of the disease. Even with potent FLT3 inhibition, the disease persists within the bone marrow microenvironment, mainly due to bone marrow stroma activating parallel signaling pathways that maintain pro-survival factors. BET inhibitors suppress pro-survival factors such as MYC and BCL2, but these drugs thus far have shown only limited single-agent clinical potential. We demonstrate here, using pre-clinical and clinical correlative studies, that the novel 4-azaindole derivative, PLX51107, has BET-inhibitory activity in vitro and in vivo. The combination of BET and FLT3 inhibition induces a synergistic antileukemic effect in a murine xenograft model of FLT3-ITD AML, and against primary FLT3-ITD AML cells co-cultured with bone marrow stroma. Using suppression of MYC as a surrogate for BET inhibition, we demonstrate BET inhibition in human patients. The short plasma half-life of PLX51107 results in intermittent target inhibition to enable tolerability while overcoming the protective effect of the microenvironment. Mechanistically, the synergistic cytotoxicity is associated with suppression of key survival genes such as MYC. These data provide the scientific rationale for a clinical trial of a BET plus FLT3 inhibitor for the treatment of relapsed/refractory FLT3-ITD AML. A clinical trial of PLX51107 as monotherapy in patients with different malignancies is underway and will be reported separately.

BACKGROUND: Diffuse Large B Cell Lymphoma (DLBCL) is the most common and most aggressive subtype of Non-Hodgkin Lymphoma. (Blood PMID: 9166827) Despite significant advances, treatment survival remains heterogenous due to biologic differences and perhaps ethnic and racial disparities. Multiple epidemiological studies have evaluated racial differences, mainly comparing African Americans (AA) with Non-Hispanic (NH), showing AA patients have a 10-20% higher risk of death. (BMC PMID: 21073707, Leuk PMID: 22800091, Cancer PMID: 24048801) A recent study showed how socioeconomic factors also influence patient survival and this can be linked to racial differences as well. (Blood PMID: 24705494). Small sample studies have characterized DLBCL in Hispanics (HI) but no definite conclusions have been drawn. (ASH Blood 2018 132:4867, JCO 10.1200, Blood (2019) 134 (Supplement_1): 2916). The need of larger studies to characterize survival differences establishes the basis of our population-based analysis in Texas comparing DLBCL in HI vs NH. METHODS: This is a retrospective study of a cohort of patients diagnosed with lymphoma from the Texas Cancer Registry (TCR) database. Patients with DLBCL diagnosed from 2006 to 2016 were identified by the International Classification of Diseases for Oncology Third Edition (ICD-O-3) code list. Standard demographic variables collected include gender, race, ethnicity, birthplace, occupation, dates at diagnosis and death, primary payer at diagnosis, subtype of lymphoma, stage, type of treatment, poverty index, and vitality status among others. Categorical outcomes were summarized with frequencies and percentages and age (years) was the only continuously distributed outcome with the mean and standard deviation. The significance of variation in the distribution of categorical outcomes with ethnicity (HI, NH) was assessed with Fisher's Exact tests or Pearson's Chi-square tests as appropriate; age was assessed with T-tests or Wilcoxon tests as appropriate. Survival time was measured in years from date of primary diagnosis to date of death. Patients not coded as dead were considered censored on survival time at the date last seen. Survival distributions were described with Kaplan-Meier curves and significance of variation in median survival with ethnicity was assessed with log rank testing. At risk tables were computed based on the Kaplan-Meier estimate of the survival curve. All statistical testing was two-sided with a significance level of 5%. RESULTS: A total of 15,083 patients met inclusion criteria, with 3583 HI and 11500 NH diagnosed with DLBCL from 2006 to 2016. Demographic data was analyzed and compared between both groups, (Fig 1A). The median age of diagnosis was 61.7 on HI population and 65 on the NH. Among the HI population most of the patients were of Mexican origin (25%). HI have a higher percentage (24%) of non-insured or Medicaid than NH (8%) with a significant p value of <0.001 and a statistically significant higher poverty index within HI with 54% living on a 20-100% poverty land. Staging was similar between both groups. Most of the patients, 46% of HI and 45% of NH, have a stage III-IV grade DLBCL. The NH population received more treatment with chemotherapy 4% compared to 2% of the HI group, but this difference was not statistically significant. Both groups received similar treatments with bone marrow transplant, or radiation. The median survival time was similar between HI and NH, 4.4 and 4.3 years respectively. Survival probability at 2, 5 and 10 years for HI was 0.59 (CI 0.576,0.611), 0.48 (CI 0.467, 0.506) and 0.301 (CI 0.265,0.34) respectively. For NH the survival probability was similar, 0.602 (CI 0.592,0.611), 0.473 (CI 0.463,0484) and 0.242 (CI 0.223,0.262) respectively (Fig 1B). The overall survival probability at 10 years did not show a statistically significant difference for HI vs NH (p-value 0.46) (Fig 1C). CONCLUSION. Despite demographic disparities between HI and NH, and statistically significant differences with more HI patients uninsured and a higher index of poverty land; there was no significant distinction in overall survival in patients with DLBCL. The findings suggest no impact of ethnicity to that regard. Disclosures Diaz Duque: ADCT Therapeutics: Research Funding; Molecular Templates: Research Funding; AstraZeneca: Research Funding; Hutchinson Pharmaceuticals: Research Funding; Seattle Genetics: Speakers Bureau; Verastem: Speakers Bureau; AbbVie: Speakers Bureau.

Subsets of non-acute promyelocytic leukemia (APL) acute myelogenous leukemia (AML) exhibit aberrant retinoid signaling and demonstrate sensitivity to retinoids in vitro. We present the results of a phase 1 dose-escalation study that evaluated the safety, pharmacodynamics, and efficacy of IRX195183, a novel retinoic acid receptor α agonist, in patients with relapsed or refractory myelodysplastic syndrome (MDS) or AML. In this single center, single arm study, eleven patients with relapsed or refractory MDS/AML were enrolled and treated. Oral IRX195183 was administered at two dose levels: 50 mg daily or 75 mg daily for a total of two 28-day cycles. Patients with stable disease or better were allowed to continue on the drug for four additional 28-day cycles. Common adverse events included hypertriglyceridemia, fatigue, dyspnea, and edema. Three patients at the first dose level developed asymptomatic Grade 3 hypertriglyceridemia. The maximally tolerated dose was not reached. Four of the eleven patients had (36%) stable disease or better. One had a morphological complete remission with incomplete hematologic recovery while on the study drug. Two patients had evidence of in vivo leukemic blast maturation, as reflected by increased CD38 expression. In a pharmacodynamics study, plasma samples from four patients treated at the lowest dose level demonstrated the capacity to differentiate leukemic cells from the NB4 cell line in vitro. These results suggest that IRX195183 is safe, achieves biologically meaningful plasma concentrations and may be efficacious in a subset of patients with MDS/AML. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02749708.

We evaluated standard-of-care (SOC) treatment with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML) harboring internal tandem duplication (ITD) in FLT3 . Adults (aged 18–70 years) who received alloHSCT in first complete remission, had achieved hematologic recovery, and were transfusion independent were randomized to receive SOC with or without midostaurin (50 mg twice daily) continuously in twelve 4-week cycles. The primary endpoint was relapse-free survival (RFS) 18 months post-alloHSCT. Sixty patients were randomized (30/arm); 30 completed all 12 cycles (midostaurin + SOC, n = 16; SOC, n = 14). The estimated 18-month RFS (95% CI) was 89% (69–96%) in the midostaurin arm and 76% (54–88%) in the SOC arm (hazard ratio, 0.46 [95% CI, 0.12–1.86]; P = 0.27); estimated relapse rates were 11% and 24%, respectively. Inhibition of FLT3 phosphorylation to <70% of baseline (achieved by 50% of midostaurin-treated patients) was associated with improved RFS. The most common serious adverse events were diarrhea, nausea, and vomiting. Rates of graft-vs-host disease were similar between both arms (midostaurin + SOC, 70%; SOC, 73%). The addition of midostaurin maintenance therapy following alloHSCT may provide clinical benefit in some patients with FLT3 -ITD AML. (ClinicalTrials.gov identifier: NCT01883362).

Background Burkitt lymphoma (BL) is a rare but highly aggressive B cell neoplasm, with treatment success rates exceeding 80% in the United States (US) (Blood, PMC:3682339). Although there are different presentations of BL, the treatment and prognosis are quite similar among them (Blood, PMID:15265787). Trends in outcomes of BL have been previously reported, however, sub-analysis for minorities like Hispanics (HI), have not been widely studied. Understanding ethnic disparities in outcomes and patterns of care are crucial given the growth of HI in the US (APMIS, PMID:23607450). There is an unmet need in this field; therefore, this population-based study aims to help understand the impact of ethnicity in clinical outcomes for BL. Material and Methods A retrospective analysis of patients diagnosed with BL recorded in the Texas Cancer Registry was carried out. Inclusion criteria was histopathologic proven BL using the International Classification of Diseases for Oncology Third Edition (ICD-O-3) code list. Patients were divided in HI and non-Hispanics (NH) for comparison. Key demographic, socioeconomic, clinical, and survival outcome variables were reviewed. All statistical testing was determined using Fisher's Exact test, Pearson's Chi-square test, T-test or Wilcoxon test, as appropriate. Survival analysis was calculated in years from date of primary diagnosis to date of death or last date of follow up. Survival distributions were described with Kaplan-Meier curves and significance of variation in median survival with ethnicity was assessed with log rank testing. All statistical testing was two-sided with a significance level of 5%. The R language [R Core Team (2013). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria] was used throughout. Results From 2006-2016, 896 patients (HI: n=275, NH: n=621) were diagnosed with BL. The median age at diagnosis for HI was 41 years vs 44 for NH [p-value 0.05]. Male sex predominated for HI and NH. Origin for HI was mainly Spain, Mexico and Central/South America. Both HI and NH were mainly identified as white; other races included black, asian and Native American [p-value <0.001]. For HI, the bracket of poverty indicator that prevailed was 20-100%; while majority of NH were in 10-19.99% [p-value <0.001]. There was a statistical significance regarding the primary payer at diagnosis [p-value <0.001]. HI had a similar distribution among private insurance (PI), Medicaid, Medicare and not insured/self-pay; while NH had primarily PI. The greatest proportion of HI and NH where located in the metropolitan, non-border area. The majority of HI and NH were diagnosed at stage III-IV [p-value 0.459]. Treatment at diagnosis showed a similar pattern for HI and NH, choosing mainly chemotherapy. For both groups, most of the patients did not undergo transplant or radiation (Figure1A). The median survival time for HI was 4.2 years and for NH was 7.0 years. Survival probability at 2, 5 and 10 years for HI was 0.53 (CI=0.467,0.599), 0.50 (CI=0.484,0.573) and 0.33 (CI=0.213,0.515), respectively. For NH it was 0.60 (CI=0.568,0.65), 0.53 (CI=0.385,0.506) and 0.44 (0.385,0.506), respectively (Figure1B). The overall survival probability at 10 years did not show a statistically significant difference for HI vs NH [p-value 0.12] (Figure1C). Conclusions Survival analysis at 10 years shows similar outcomes for HI vs NH; however, significant differences were observed in demographics and sociocultural variables. HI were diagnosed at a younger age, predominantly of Spanish origin and white race. More HI were uninsured compared to NH, as well as their poverty index was statistically higher. The fact that no variation was reported in overall survival may be explained by the use of standardized treatment. From our analysis, racial or economical variations do not seem to affect oncological outcomes in BL for HI in the US. Disclosures Diaz Duque: ADCT Therapeutics: Research Funding; Molecular Templates: Research Funding; AstraZeneca: Research Funding; Hutchinson Pharmaceuticals: Research Funding; Seattle Genetics: Speakers Bureau; Verastem: Speakers Bureau; AbbVie: Speakers Bureau.

Innate lymphoid cells (ILCs) are generated early during ontogeny and persist predominantly as tissue-resident cells. Here, we examined how ILCs are maintained and renewed within tissues. We generated a single cell atlas of lung ILC2s and found that Il18r1+ ILCs comprise circulating and tissue-resident ILC progenitors (ILCP) and effector-cells with heterogeneous expression of the transcription factors Tcf7 and Zbtb16, and CD103. Our analyses revealed a continuous differentiation trajectory from Il18r1+ ST2- ILCPs to Il18r- ST2+ ILC2s, which was experimentally validated. Upon helminth infection, recruited and BM-derived cells generated the entire spectrum of ILC2s in parabiotic and shield chimeric mice, consistent with their potential role in the renewal of tissue ILC2s. Our findings identify local ILCPs and reveal ILCP in situ differentiation and tissue adaptation as a mechanism of ILC maintenance and phenotypic diversification. Local niches, rather than progenitor origin, or the developmental window during ontogeny, may dominantly imprint ILC phenotypes in adult tissues.

BACKGROUND: Diffuse Large B Cell Lymphoma (DLBCL) is the most common hematologic malignancy in adults. Unfortunately, more than one-third of patients will fail first line therapy, highlighting the need for a better understanding of biology of DLBCL and whether biological variables with clinical significance have the same impact across different ethnicities. Two clinically applicable prognostic models in DLBCL are the cell-of-origin (COO) classifier and the MYC/BCL2 expression pattern. The former classifies DLBCL in germinal center B-cell (GCB) and non-GCB subtypes. Patients diagnosed with GCB-like DLBCLs have significantly better outcome than those with non-GCB-like lymphomas. More recently, IHC-based quantification of MYC/BCL2 in DLBCL biopsies was shown to also impart prognostic value, with tumors positive for both markers, named dual-expresser (DE) DLBCL, harboring a particularly poor outcome. Moreover, DLBCL cases are further characterized into "double hit" (DH) or "triple hit" (TH) based on the rearrangements of MYC and BCL2, MYC and BCL6 or MYC, BCL2 and BCL6, which by far exhibit the poorest outcome. The paucity of data comparing the DLBCL biological variables and outcomes among different ethnicities establishes the basis of our analysis at the only NCI-designated cancer center of south Texas within a Hispanic (HI) predominant patient population. METHODS: This is an observational study where we identified patients with diagnosis of Lymphoma (Hodgkin and Non-Hodgkin) by International Classification of Diseases (ICD) codes. Only patients with DLBCL were retrospectively analyzed; the patients received care at UT Health San Antonio between 2008-2018. Key variables for each patient included age, gender, race/ethnicity, comorbidities, insurance status, stage, treatment received, characterization by COO, IHC markers, molecular rearrangements, outcome at 3 and 5 years and vitality status in 2018. Continuously distributed outcomes were summarized with the mean and standard deviation and categorical outcomes were summarized with frequencies and percentages. The primary endpoint is to compare whether there are differences between HI and non-Hispanics (NH) with respect to biologic variables and hence their outcomes. The study was approved by the local Institutional Review Board. The findings will be available to patients, funders and medical community through traditional publishing and social media. RESULTS: A total of 196 newly diagnosed patients met inclusion criteria, with 115 HI (59%) and 81 NH (41%). HI have a higher percentage (40%) of non-insured, Medicaid or a financial assistance program than NH (28%) . We were able to identify 172 patients with either GCB or non-GCB type. From our HI, 55 (48%) patients were GCB and 46 (40%) were non-GCB while within NH, 47 (58%) patients were GCB and 24 (30%) non-GCB. We gathered IHC data on 147 patients; DE with BCL2/MYC was found in 9 (8%) of HI patients and 14 (17%) of NH patients. There was around the same percentage of unavailable COO and IHC data for both groups, 12% and 25% respectively. Only 11 patients were identified as DH or TH. Among HI, 4 were DH and 1 was TH; while in NH, 5 were DH and 1 was TH (Fig 1A). When looking at survival, as of today 63% of patients are still alive in both groups. Among alive HI, 34 (62%) patients are of GCB origin and 31 (67%) are of non-GCB origin. On the other hand; within the alive NH patients, 34 (72% of GCB positive) are of GCB origin and 11 (46%) are of non-GCB origin (Fig 1B, 1C). Also, DE status apparently had no major difference in survival across ethnicities since 7 (50%) NH remain alive versus 4 (44%) HI (Fig 1D, 1E). Lastly, within HI there are only 2 DH and no TH patients alive, while within NH there are 3 DH patients alive 1 TH patient who is still not 3 years out. CONCLUSION: HI have similar and well-balanced molecular characteristics and outcomes compared to NH. As opposed to what we thought, the COO classifier does not seem to predict differences in prognosis in HI as they appear to have equal outcome irrespective of GCB vs non-GCB origin. The prognosis in HI with overexpression of MYC/BCL2 is bad and even worse if DH or TH as historically seen in NH. To our knowledge this is the first retrospective review that includes the largest Hispanic cohort in North America. Figure 1 Disclosures Hernandez: ASH MRHAP: Research Funding.

An intriguing aspect of the clinical activity of FMS-like tyrosine kinase 3 inhibitors (FLT3 TKIs) is their apparent higher activity against peripheral blasts from FLT3/internal tandem duplication (ITD) acute myeloid leukemia than marrow disease in the same patients. Accordingly, studies showed that the bone marrow microenvironment plays a role in FLT3 TKI resistance, although the underlying mechanisms are unclear. We recently identified a previously undescribed mechanism by which the bone marrow microenvironment can contribute to drug resistance: expression of cytochrome P450 enzymes (CYPs). In fact, bone marrow stromal cells (BMSCs) expressed most CYPs, including CYP3A4. Because hepatic CYP3A4 plays a role in the inactivation of several FLT3 TKIs, we explored the potential role of CYP3A4 in bone marrow microenvironment-mediated FLT3 TKI resistance. We found that CYP3A4 plays a major role in BMSC-mediated inhibition in the activity of 3 different FLT3 TKIs (sorafenib, quizartinib, and gilteritinib) against FLT3/ITD acute myeloid leukemia (AML). Furthermore, clarithromycin, a clinically active CYP3A4 inhibitor, significantly reversed the protective effects of BMSCs. We show, for the first time, that bone marrow stromal CYP3A4 contributes to FLT3 TKI resistance in the bone marrow. These results suggest that combining FLT3 TKIs with CYP3A4 inhibitors could be a promising strategy toward improving the activity of FLT3 TKIs.

The bone marrow (BM) microenvironment contributes to drug resistance in acute myeloid leukaemia (AML) and multiple myeloma (MM). We have shown that the critical drug metabolizing enzymes cytochrome P450 (CYP) 3A4 and cytidine deaminase (CDA) are highly expressed by BM stroma, and play an important role in this resistance to chemotherapy. However, what factors influence the chemoprotective capacity of the BM microenvironment, specifically related to CYP3A4 and CDA expression, are unknown. In this study, we found that the presence of AML cells decreases BM stromal expression of CYP3A4 and CDA, and this effect appears to be at least partially the result of cytokines secreted by AML cells. We also observed that stromal CYP3A4 expression is up-regulated by drugs commonly used in AML induction therapy, cytarabine, etoposide and daunorubicin, resulting in cross-resistance. Cytarabine also up-regulated CDA expression. The up-regulation of CYP3A4 associated with disease control was reversed by clarithromycin, a potent inhibitor of CYP3A4. Our data suggest that minimal residual disease states are characterized by high levels of stromal drug metabolizing enzymes and thus, strong microenvironment-mediated drug resistance. These results further suggest a potential role for clinically targeting drug metabolizing enzymes in the microenvironment.

BACKGROUND Cabozantinib, a tyrosine kinase inhibitor of FMS‐like tyrosine kinase 3 (FLT3), MET, AXL, vascular endothelial growth factor receptor, and KIT, is approved for use in multiple malignancies. We assessed the safety and tolerability of cabozantinib in AML, given up‐regulation of multiple relevant pathways. METHODS Adults were eligible if they were 18 years old or older with relapsed/refractory AML or if they were 70 years old or older with newly diagnosed AML but were ineligible for conventional therapy. Cabozantinib was administered in 28‐day cycles, and dose escalation occurred via cohorts. A pharmacodynamic evaluation of serial plasma samples via a plasma inhibitory assay (PIA) was used to assess FLT3‐inhibitory activity in FLT3‐mutant cell lines. RESULTS Among 18 patients enrolled, 5 were found to harbor FLT3/ITD mutations. Sixteen patients (89%) had relapsed/refractory AML, and most were treated with 2 or more lines of prior treatment. No dose‐limiting toxicities (DLTs) were detected at the first dose level (40 mg daily), but 2 patients experienced DLTs at the next level (60 mg daily). The remaining patients were then dosed at 40 mg daily, the maximum tolerated dose (MTD). Additional grade 2 or higher toxicities, possibly/probably related to cabozantinib, included fatigue, nausea, transaminitis, and electrolyte imbalance. No patients had a marrow response according to formal criteria, but 4 had peripheral blast reductions; 2 of these 4 patients transiently cleared circulating blasts. One patient experienced a reduction in marrow blasts, and 1 had stable disease. The FLT3‐inhibitory activity of plasma samples, as assessed with the PIA, revealed potent and sustained inhibition in FLT3/ITD and, notably, F691 tyrosine kinase domain (TKD)–mutant cells. CONCLUSIONS Cabozantinib is well tolerated in AML patients at an MTD of 40 mg daily and is a potent inhibitor of FLT3/ITD‐ and F691 TKD–altered tyrosine kinases. Cancer 2018;124:306‐14. © 2017 American Cancer Society .

In recent years, innate lymphoid cells (ILCs) have emerged as key mediators of protection and repair of mucosal surfaces during infection. The lung, a dynamic mucosal tissue that is exposed to a plethora of microbes, is a playground for respiratory infection-causing pathogens which are not only a major cause of fatalities worldwide, but are also associated with comorbidities and decreased quality of life. The lung provides a rich microenvironment to study ILCs in the context of innate protection mechanisms within the airways, unraveling their distinct functions not only in health but also in disease. In this review, we discuss how pulmonary ILCs play a role in protection against viral, parasitic, bacterial, and fungal challenge, along with the mechanisms underlying this ILC-mediated immunity.

To the editor: FLT3-activating mutations are one of the most frequent genetic aberrations in acute myeloid leukemia (AML).[1][1] Internal tandem duplication (FLT3-ITD) mutations are associated with the worst prognosis, whereas tyrosine kinase domain (FLT3/TKD) mutations have an uncertain prognostic

Background