Management of Advanced Systemic Mastocytosis and Associated Myeloid Neoplasms.

Advanced systemic mastocytosis (AdvSM) is a heterogeneous group of disorders characterized by neoplastic mast cell-related organ damage and frequently associated with a myeloid neoplasm. The 3 clinical entities that comprise AdvSM are aggressive SM (ASM), SM-associated hematologic neoplasm, and mast cell leukemia. A gain-of-function KIT D816 V mutation is the primary oncogenic driver found in about 90% of all patients with AdvSM. Midostaurin, an oral multikinase inhibitor with activity against KIT D816V, and avapritinib, an oral selective KIT D816V inhibitor are approved for AdvSM.

Trends in overall mortality among US veterans with primary myelofibrosis.

BACKGROUND: Primary myelofibrosis [PMF] is a myeloproliferative neoplasm associated with reduced overall survival (OS). Management strategies for PMF have evolved over the last two decades, including approval of ruxolitinib as the first Janus kinase 1 (JAK1)/JAK2 inhibitor for patients with intermediate or high-risk myelofibrosis. This study assessed changes in mortality before and after ruxolitinib approval, independent of ruxolitinib treatment. METHODS: This retrospective study investigated mortality trends among US veterans with PMF in 2 time periods, pre-ruxolitinib approval (01/01/2007-12/31/2010) and post-ruxolitinib approval (01/01/2015-09/30/2018). Deidentified patient-level data were extracted from US Veterans Health Administration (VHA) databases using PMF diagnosis codes; index was the first PMF diagnosis date. The analysis included adults with ≥2 PMF claims during the analysis periods who were continuously enrolled in the VHA plan 1 calendar year prior to and 6 months post-index and had ≥1 available International Prognostic Scoring System (IPSS) risk factor (available factors were age > 65, hemoglobin < 10 g/dL, and white blood cell count > 25 × 109/L; each counted as one point). Patients with ≥1 MF diagnosis for 12 months before the index period were excluded. Ruxolitinib treatment was not a requirement to be included in the post-ruxolitinib approval cohort. Mortality rates and OS were estimated using the Kaplan-Meier approach; all-cause mortality hazard ratio was estimated using univariate Cox regression. RESULTS: The pre- and post-ruxolitinib approval cohorts included 193 and 974 patients, respectively, of which 80 and 197 had ≥2 IPSS risk factors. Ruxolitinib use in the post-ruxolitinib cohort was 8.5% (83/974). At end of follow-up, median (95% CI) OS was significantly shorter in the pre-ruxolitinib cohort (1.7 [1.2-2.6] years vs not reached [3.4-not reached]; P < 0.001). Overall mortality rates for the pre- versus post-ruxolitinib approval cohorts were 79.8% versus 47.3%, respectively, and overall risk of death was 53% lower in the post-ruxolitinib period (hazard ratio, 0.47; 95% CI, 0.37-0.58; P < 0.001). Mortality rates were lower among patients with < 2 vs ≥2 IPSS risk factors. CONCLUSIONS: Although veterans with PMF have high overall mortality rates, and results in this population might not be generalizable to the overall population, there was a significant lowering of mortality rate in the post-ruxolitinib period.

Avapritinib versus Placebo in Indolent Systemic Mastocytosis.

BACKGROUND: Indolent systemic mastocytosis (ISM) is a clonal mast-cell disease driven by the KIT D816V mutation. We assessed the efficacy and safety of avapritinib versus placebo, both with best supportive care, in patients with ISM. METHODS: We randomized patients with moderate to severe ISM (total symptom score [TSS] of ≥28; scores range from 0 to 110, with higher numbers indicating more severe symptoms) two to one to avapritinib 25 mg once daily (n=141) or placebo (n=71). The primary end point was mean change in TSS based on the 14-day average of patient-reported severity of 11 symptoms. Secondary end points included reductions in serum tryptase and blood KIT D816V variant allele fraction (≥50%), reductions in TSS (≥50% and ≥30%), reduction in bone marrow mast cells (≥50%), and quality of life measures. RESULTS: From baseline to week 24, avapritinib-treated patients had a decrease of 15.6 points (95% CI, −18.6 to −12.6) in TSS compared to a decrease of 9.2 points (−13.1 to −5.2) in the placebo group; P<0.003. From baseline to Week 24, 76/141 patients (54%; 45% to 62%) in the avapritinib group compared to 0/71 patients in the placebo group achieved a ≥50% reduction in serum tryptase level; P<0.001. Edema and increases in alkaline phosphatase were more common with avapritinib than placebo; there were few treatment discontinuations because of adverse events. CONCLUSIONS: In this trial, avapritinib was superior to placebo in reducing uncontrolled symptoms and mast-cell burden in patients with ISM. The long-term safety and efficacy of this approach for patients with ISM remain the focus of the ongoing trial. (Funded by Blueprint Medicines Corporation; ClinicalTrials.gov number, NCT03731260.)

Hematocrit, White Blood Cells, and Thrombotic Events in the Veteran Population With Polycythemia Vera.

Background: Patients with polycythemia vera (PV), a chronic myeloproliferative neoplasm, have a greater morbidity and mortality risk than the general population, largely due to a high incidence of thrombotic events. Observations: Two recently published retrospective analyses from Parasuraman and colleagues used Veterans Health Administration (VHA) data to replicate, in a real-world population, findings from the prospective, randomized Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) study. In the CYTO-PV study, hematocrit (Hct) level and white blood cell (WBC) count were shown to be independently associated with thrombotic event risk in patients with PV. In the VHA analysis, patients with Hct levels < 45% were found to have a significantly lower rate of thrombotic events compared to those with levels ≥ 45% (hazard ratio [HR], 1.61; P = .04). For WBC counts and thrombosis, patients with WBC ≥ 8.5 × 109/L were found to have a higher rate of thrombotic events compared to the reference cohort of WBC < 7 × 109/L (HR, 1.47; P < .01), and the rates were higher for those with WBC ≥ 11 × 109/L (HR 1.87; P < .001). Conclusions: The results from these analyses suggest the need for managing Hct appropriately to maintain levels < 45% and offer further support for the consideration of WBC counts in determining risk of thrombotic events. Studies are needed to clearly establish an optimal WBC count to inform updates to treatment guidelines.

Large-Scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers.

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoietic-associated gene mutations in a person without evidence of hematologic malignancy. We sought to identify additional cancer-presenting mutations useable for CHIP detection by performing a data mining analysis of 48 somatic mutation studies reporting mutations at diagnoses of 7,430 adult and pediatric patients with hematologic malignancies. Following extraction of 20,141 protein-altering mutations, we identified 434 significantly recurrent mutation hotspots, 364 of which occurred at loci confidently assessable for CHIP. We then performed an additional large-scale analysis of whole exome sequencing data from 4,538 persons belonging to three non-cancer cohorts for clonal mutations. We found the combined cohort prevalence of CHIP with mutations identical to those reported at blood cancer mutation hotspots to be 1.8%, and that some of these CHIP mutations occurred in children. Our findings may help to improve CHIP detection and pre-cancer surveillance for both children and adults.

Thrombotic, inflammatory, and HIF-regulated genes and thrombosis risk in polycythemia vera and essential thrombocythemia.

Thrombosis is a major cause of morbidity and mortality in polycythemia vera (PV) and essential thrombocythemia (ET). The pathophysiology of thrombosis in these disorders remains unclear, and we hypothesized that upregulation of thrombotic, inflammatory, and hypoxia-inducible factor (HIF)-regulated genes may play a role in it. We performed unbiased RNA sequencing in granulocytes and platelets of PV patients and found differential expression of several thrombotic, inflammatory, and HIF-regulated genes. The expression of many of these genes positively correlated with JAK2 expression and JAK2V617F allelic burden. We then validated these findings by quantitative polymerase chain reaction analyses of selected gene transcripts in a larger number of PV and ET granulocytes and platelets (58 patients) and in 28 controls, and we compared these findings in patients with and without thrombosis. The study included 29 females and 29 males; of these, 28 had a history of thrombosis. We found that transcripts of several selected genes were upregulated in patients with PV or ET compared with controls. In granulocytes, the expression levels of F3, SELP, VEGFA, and SLC2A1 were significantly higher in patients with a history of thrombosis compared with those who did not have thrombosis. Patients with a history of thrombosis have significantly higher expression of IL1RAP (P < .05) in platelets compared with those without thrombosis. Our study confirms the presence of a thrombo-inflammatory state and augmented HIF activity in PV and ET and its role in thrombosis. These data may provide the background for targeted therapies in PV and ET.

Familial MPN Predisposition.

Chronic myeloproliferative neoplasms (MPN) characteristically arise from a somatic mutation in the pluripotent hematopoietic stem cell, and most common recurring mutations are in the JAK2, CALR, and cMPL genes. However, these mutations are not founder mutations, but mainly drive the disease phenotype and a pre-existing germline predisposition has been long speculated, but has not been clearly defined to date. Genome-wide association studies in family clusters of MPN have identified a number of genetic variants that are associated with increased germline risk for developing clonal MPN. The strongest association discovered so far is the presence of JAK2 46/1 haplotype, and subsequently, many studies have found additional variants in other genes, most notably in TERT gene. However, these still account for a small fraction of familial MPN, and more in-depth studies including whole genome sequencing are needed to gain better insight into familial genetic predisposition of clonal MPNs.

Evolutionary history of Tibetans inferred from whole-genome sequencing.

The indigenous people of the Tibetan Plateau have been the subject of much recent interest because of their unique genetic adaptations to high altitude. Recent studies have demonstrated that the Tibetan EPAS1 haplotype is involved in high altitude-adaptation and originated in an archaic Denisovan-related population. We sequenced the whole-genomes of 27 Tibetans and conducted analyses to infer a detailed history of demography and natural selection of this population. We detected evidence of population structure between the ancestral Han and Tibetan subpopulations as early as 44 to 58 thousand years ago, but with high rates of gene flow until approximately 9 thousand years ago. The CMS test ranked EPAS1 and EGLN1 as the top two positive selection candidates, and in addition identified PTGIS, VDR, and KCTD12 as new candidate genes. The advantageous Tibetan EPAS1 haplotype shared many variants with the Denisovan genome, with an ancient gene tree divergence between the Tibetan and Denisovan haplotypes of about 1 million years ago. With the exception of EPAS1, we observed no evidence of positive selection on Denisovan-like haplotypes.

Gain-of-function EGLN1 prolyl hydroxylase (PHD2 D4E:C127S) in combination with EPAS1 (HIF-2α) polymorphism lowers hemoglobin concentration in Tibetan highlanders.

Tibetans have lived at high altitude for generations and are thought to be genetically adapted to hypoxic environments. Most are protected from hypoxia-induced polycythemia, and a haplotype of EPAS1, encoding hypoxia-inducible factor (HIF-2α), has been associated with lower hemoglobin levels. We earlier reported a Tibetan-specific EGLN1 haplotype encoding PHD2 which abrogates HIF augmentation in hypoxia. We genotyped 347 Tibetan individuals from varying altitudes for both the Tibetan-specific EGLN1 haplotype and 10 candidate SNPs in the EPAS1 haplotype and correlated their association with hemoglobin levels. The effect of the EGLN1 haplotype on hemoglobin exhibited age dependency at low altitude, while at higher altitudes, it showed a trend to lower hemoglobin levels in the presence of the Tibetan-selected EPAS1 rs142764723 C/C allele. The observed gene-environment and gene-gene interactions and the moderate effect of the EGLN1 and EPAS1 haplotypes on hemoglobin indicate that other modifiers exist. It remains to be determined whether a blunting of erythropoiesis or other physiological consequences of HIF downregulation are the primary drivers of these genetic adaptations among Tibetans. KEY MESSAGE: Most Tibetans are protected from polycythemia while living in high altitude. An EGLN1 co-adapted haplotype, EGLN1 c.12C>G, c.380G>C is uniquely Tibetan. The Tibetan EPAS1 haplotype has introgressed from the Denisovan genome. While EGLN1 and EPAS1 genotypes lower Hb, this study indicates additional Hb modifiers.

Evolutionary selected Tibetan variants of HIF pathway and risk of lung cancer.

Tibetans existed in high altitude for ~25 thousand years and have evolutionary selected unique haplotypes assumed to be beneficial to hypoxic adaptation. EGLN1/PHD2 and EPAS1/HIF-2α, both crucial components of hypoxia sensing, are the two best-established loci contributing to high altitude adaptation. The co-adapted Tibetan-specific haplotype encoding for PHD2:p.[D4E/C127S] promotes increased HIF degradation under hypoxic conditions. The Tibetan-specific 200 kb EPAS1 haplotype introgressed from an archaic human population related to Denisovans which underwent evolutionary decay; however, the functional variant(s) responsible for high-altitude adaptation at EPAS1/HIF-2α have not yet been identified. Since HIF modulates the behavior of cancer cells, we hypothesized that these Tibetan selected genomic variants may modify cancer risk predisposition. Here, we ascertained the frequencies of EGLN1D4E/C127S and EGLN1C127S variants and ten EPAS1/HIF-2α variants in lung cancer patients and controls in Nepal, whose population consists of people with Indo-Aryan origin and Tibetan-related Mongoloid origin. We observed a significant association between the selected Tibetan EGLN1/PHD2 haplotype and lung cancer (p=0.0012 for D4E, p=0.0002 for C127S), corresponding to a two-fold increase in lung cancer risk. We also observed a two-fold or greater increased risk for two of the ten EPAS1/HIF-2α variants, although the association was not significant after correcting for multiple comparisons (p=0.12). Although these data cannot address the role of these genetic variants on lung cancer initiation or progression, we conclude that some selected Tibetan variants are strongly associated with a modified risk of lung cancer.

A Genome-Wide Search for Greek and Jewish Admixture in the Kashmiri Population.

The Kashmiri population is an ethno-linguistic group that resides in the Kashmir Valley in northern India. A longstanding hypothesis is that this population derives ancestry from Jewish and/or Greek sources. There is historical and archaeological evidence of ancient Greek presence in India and Kashmir. Further, some historical accounts suggest ancient Hebrew ancestry as well. To date, it has not been determined whether signatures of Greek or Jewish admixture can be detected in the Kashmiri population. Using genome-wide genotyping and admixture detection methods, we determined there are no significant or substantial signs of Greek or Jewish admixture in modern-day Kashmiris. The ancestry of Kashmiri Tibetans was also determined, which showed signs of admixture with populations from northern India and west Eurasia. These results contribute to our understanding of the existing population structure in northern India and its surrounding geographical areas.

Intracranial Inflammatory Myofibroblastic Tumor with Sarcomatous Local Recurrence.

CASE DESCRIPTION: A 20-year-old woman presented with a rare intracranial inflammatory myofibroblastic tumor (IMT) manifesting as headache and insomnia. Magnetic resonance imaging showed a tumorous lesion with heterogeneous enhancement at the right temporal lobe, as well as perifocal edema with midline shift. The tumor was totally resected with the margin free. Pathologic examination showed IMT with myofibroblastic cells admixed with collagen fibers. Sarcomatous change in morphology was observed in tumor recurrence within 7 months. CONCLUSIONS: Surgical resection and whole brain radiation are recommended in patients with IMT.

A genetic mechanism for Tibetan high-altitude adaptation.

Tibetans do not exhibit increased hemoglobin concentration at high altitude. We describe a high-frequency missense mutation in the EGLN1 gene, which encodes prolyl hydroxylase 2 (PHD2), that contributes to this adaptive response. We show that a variant in EGLN1, c.[12C>G; 380G>C], contributes functionally to the Tibetan high-altitude phenotype. PHD2 triggers the degradation of hypoxia-inducible factors (HIFs), which mediate many physiological responses to hypoxia, including erythropoiesis. The PHD2 p.[Asp4Glu; Cys127Ser] variant exhibits a lower K(m) value for oxygen, suggesting that it promotes increased HIF degradation under hypoxic conditions. Whereas hypoxia stimulates the proliferation of wild-type erythroid progenitors, the proliferation of progenitors with the c.[12C>G; 380G>C] mutation in EGLN1 is significantly impaired under hypoxic culture conditions. We show that the c.[12C>G; 380G>C] mutation originated ∼8,000 years ago on the same haplotype previously associated with adaptation to high altitude. The c.[12C>G; 380G>C] mutation abrogates hypoxia-induced and HIF-mediated augmentation of erythropoiesis, which provides a molecular mechanism for the observed protection of Tibetans from polycythemia at high altitude.

High altitude genetic adaptation in Tibetans: no role of increased hemoglobin-oxygen affinity.

High altitude exerts selective evolutionary pressure primarily due to its hypoxic environment, resulting in multiple adaptive responses. High hemoglobin-oxygen affinity is postulated to be one such adaptive change, which has been reported in Sherpas of the Himalayas. Tibetans have lived on the Qinghai-Tibetan plateau for thousands of years and have developed unique phenotypes, such as protection from polycythemia which has been linked to PDH2 mutation, resulting in the downregulation of the HIF pathway. In order to see if Tibetans also developed high hemoglobin-oxygen affinity as a part of their genetic adaptation, we conducted this study assessing hemoglobin-oxygen affinity and their fetal hemoglobin levels in Tibetan subjects from 3 different altitudes. We found normal hemoglobin-oxygen affinity in all subjects, fetal hemoglobin levels were normal in all except one and no hemoglobin variants in any of the subjects. We conclude that increased hemoglobin-oxygen affinity or increased fetal hemoglobin are not adaptive phenotypes of the Tibetan highlanders.

Assessment of prognostic factors after primary tumor resection in metastatic colon cancer patients: a Veteran's Affairs Central Cancer Registry (VACCR) analysis, 1995-2008.

BACKGROUND: Resection of the primary tumor in metastatic colon cancer may occur for palliation of bleeding or obstruction despite distant metastases. This study evaluates clinicopathologic features that serve as prognostic markers in those patients with stage IV colon cancer who undergo resection of their primary tumor. METHODS: Retrospective analysis of stage IV colon cancer patients who underwent surgical resection of the primary tumor from 1995 to 2008 was done via the Veteran's Affairs Central Cancer Registry. Age, Charlson co-morbidity index score, extent of metastases, sex, number of lymph nodes examined, lymph node ratio (LNR), type of surgery, use of adjuvant chemotherapy, primary tumor site, and grade were studied with respect to overall survival by using log-rank and Kaplan-Meier analysis. RESULTS: There were 2,625 patients with stage IV colon cancer who had primary tumor resection. Age at diagnosis, Charlson co-morbidity index score, lymph node ratio, and use of chemotherapy were found to be independent predictors of survival by multivariate analysis. CONCLUSION: Clinicopathologic factors such as LNR, use of chemotherapy, age, co-morbidities, site of primary colon tumor, and number of sites of metastasis are all independent predictors of overall survival in patients who undergo primary colon tumor resection in the metastatic setting.