Secondary cytogenetic abnormalities in core-binding factor AML harboring inv(16) vs t(8;21)

Patients with core-binding factor (CBF) acute myeloid leukemia (AML), caused by either t(8; 21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), have higher complete remission rates and longer survival than patients with other subtypes of AML. However, similar to 40% of patients relapse, and the literature suggests that patients with inv(16) fare differently from those with t(8;21). We retrospectively analyzed 537 patients with CBF-AML, focusing on additional cytogenetic aberrations to examine their impact on clinical outcomes. Trisomies of chromosomes 8, 21, or 22 were significantly more common in patients with inv(16)/t(16;16): 16% vs 7%, 6% vs 0%, and 17% vs 0%, respectively. In contrast, del(9q) and loss of a sex chromosome were more frequent in patients with t(8;21): 15% vs 0.4% for del(9q), 37% vs 0% for loss of X in females, and 44% vs 5% for loss of Y in males. Hyperdiploidy was more frequent in patients with inv(16) (25% vs 9%, whereas hypodiploidy was more frequent in patients with t(8;21) (37% vs 3%. In multivariable analyses (adjusted for age, white blood counts at diagnosis, and KIT mutation status), trisomy 8 was associated with improved overall survival (OS) in inv(16), whereas the presence of other chromosomal abnormalities (not trisomy 8) was associated with decreased OS. In patients with t(8;21), hypodiploidy was associated with improved disease-free survival; hyperdiploidy and del(9q) were associated with improved OS. KIT mutation (either positive or not tested, compared with negative) conferred poor prognoses in univariate analysis only in patients with t(8;21)

HLA class I and II diversity contributes to the etiologic heterogeneity of non-Hodgkin lymphoma subtypes

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for: 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL=1.31, 95% CI=1.06-1.60; OR MZL=1.45, 95% CI=1.12-1.89) and class II HLA-DRB1 locus (OR DLBCL=2.10, 95% CI=1.24-3.55; OR MZL= 2.10, 95% CI=0.99-4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (p-trend<0.0001, FDR=0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes

Evaluating the use of friend or family controls in epidemiologic case-control studies

AbstractBackgroundTraditional methodologies for identifying and recruiting controls in epidemiologic case-control studies, such as random digit dialing or neighborhood walk, suffer from declining response rates. Here, we revisit the feasibility and comparability of using alternative sources of controls, specifically friend and family controls.MethodsWe recruited from a recently completed case-control study of non-Hodgkin lymphoma (NHL) among women in Los Angeles County where controls from the parent study were ascertained by neighborhood walk. We calculated participation rates and compared questionnaire responses between the friend/family controls and the original matched controls from the parent study.ResultsOf the 182 NHL case patients contacted, 111 (61%) agreed to participate in our feasibility study. 70 (63%) provided contact information for potential friend and/or family member controls. We were able to successfully contact and recruit a friend/family member for 92% of the case patients. This represented 46 friend controls and 54 family controls. Family controls significantly differed from original matched controls by sex and household income. Other characteristics were similar between friend controls and the original study’s neighborhood controls.ConclusionThe apparent comparability of neighborhood controls to friend and family controls among respondents in this study suggests that these alternative methods of control identification can serve as a complementary source of eligible controls in epidemiologic case-control studies

Multispecific Targeting with Synthetic Ankyrin Repeat Motif Chimeric Antigen Receptors

PURPOSE The outgrowth of antigen-negative variants is a significant challenge for adoptive therapy with T cells that target a single specificity. Chimeric antigen receptors (CAR) are typically designed with one or two scFvs that impart antigen specificity fused to activation and costimulation domains of T-cell signaling molecules. We designed and evaluated the function of CARs with up to three specificities for overcoming tumor escape using Designed Ankyrin Repeat Proteins (DARPins) rather than scFvs for tumor recognition. EXPERIMENTAL DESIGN A monospecific CAR was designed with a DARPin binder (E01) specific for EGFR and compared with a CAR designed using an anti-EGFR scFv. CAR constructs in which DARPins specific for EGFR, EpCAM, and HER2 were linked together in a single CAR were then designed and optimized to achieve multispecific tumor recognition. The efficacy of CAR-T cells bearing a multispecific DARPin CAR for treating tumors with heterogeneous antigen expression was evaluated in vivo. RESULTS The monospecific anti-EGFR E01 DARPin conferred potent tumor regression against EGFR$^{+}$ targets that was comparable with an anti-EGFR scFv CAR. Linking three separate DARPins in tandem was feasible and in an optimized format generated a single tumor recognition domain that targeted a mixture of heterogeneous tumor cells, each expressing a single antigen, and displayed synergistic activity when tumor cells expressed more than one target antigen. CONCLUSIONS DARPins can serve as high-affinity recognition motifs for CAR design, and their robust architecture enables linking of multiple binders against different antigens to achieve functional synergy and reduce antigen escape

Impact of region of diagnosis, ethnicity, age, and gender on survival in acute myeloid leukemia (AML)

Aim: Acute myeloid leukemia (AML) is an aggressive hematopoietic clonal disorder characterized by the increased blasts and poor survival outcome, which is mainly driven by cytogenetic and molecular abnormalities. Here, we investigated the prognostic impact of other demographic parameters on the survival outcomes in AML patients. Method: We reviewed the Surveillance, Epidemiology, and End Result (SEER) database to collect demographic information, including age, diagnosis, gender, race, and geographic region in patients with non-acute promyelocytic leukemia AML, between 2004-2008. The primary end-point of our study was 3-year overall survival (OS), which was estimated by the Kaplan-Meier method and Cox regression model. Results: A total of 13,282 patients were included in our analyses. Increasing age (HR 1.2, p < .0001), male gender (HR 1.05, p = .01), and geographic region of Midwest (HR 1.07, p=.002) were associated with inferior 3-year OS in univariate analysis, and these parameters remained independent prognostic factors in multivariate analyses. Conclusions: AML is a heterogeneous myeloid neoplasm with patient outcomes largely dictated by the cytogenetics and somatic mutations. In our study, additional demographic factors, including advanced age, male gender, and geographic region of AML diagnosis were associated with OS outcome in non-APL AML patients.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Cancer survivorship care for young adults: a risk-stratified, multicenter randomized controlled trial to improve symptoms

PurposeYoung adult (YA) cancer survivors have high rates of adverse health and psychosocial outcomes. This risk-stratified, multicenter, randomized controlled trial (RCT) compared a self-management survivorship intervention to usual care in YA survivors with symptoms of cancer-related distress, insomnia, fatigue, pain, and/or depression.MethodsEligibility included age 18-39 at diagnosis with an invasive malignancy in the previous 1-5&nbsp;years. Baseline assessment determined "high need" participants, with 2-5 elevated targeted symptoms. We randomized high need participants to intervention or usual care and offered intervention participants a survivorship clinic visit, which included mutually decided action plans for symptoms. Follow-up calls at 1 and 3&nbsp;months after the clinic visit reviewed action plan progress. Outcomes compared rates of improved symptoms for intervention vs usual care at 6&nbsp;months and 12&nbsp;months.ResultsN = 344 completed baseline assessment, with n = 147 (43%) categorized as high need and randomized. Of n = 73 randomized to the intervention, n = 42 (58%) did not attend their survivorship clinic visit. In intent-to-treat analyses, aggregate symptom scores did not differ between arms, though distress improved for 46% in the intervention arm at 6&nbsp;months compared to 18% in usual care (p = 0.03) among those with elevated distress at baseline.ConclusionsDistress improved for YAs who received self-management survivorship care. However, the study demonstrates a need for alternative strategies for providing YA survivorship care.Trial registrationNCT02192333 IMPLICATIONS FOR CANCER SURVIVORS: While YA survivors demonstrate some improved distress when provided survivorship care, to make care accessible and effective, they require options such as remote delivery of care

gamma-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma

B-cell maturation antigen (BCMA) is a validated target for chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma (MM). Despite promising objective response rates, most patients relapse, and low levels of BCMA on a subset of tumor cells has been suggested as a probable escape mechanism. BCMA is actively cleaved from the tumor cell surface by the ubiquitous multisubunit gamma-secretase (GS) complex, which reduces ligand density on tumor cells for CAR T-cell recognition and releases a soluble BCMA (sBCMA) fragment capable of inhibiting CAR T-cell function. Sufficient sBCMA can accumulate in the bone marrow of MM patients to inhibit CAR T-cell recognition of tumor cells, and potentially limit efficacy of BCMA-directed adoptive T-cell therapy. We investigated whether blocking BCMA cleavage by small-molecule GS inhibitors (GSIs) could augment BCMA-targeted CAR T-cell therapy. We found that exposure of myeloma cell lines and patient tumor samples to GSIs markedly increased surface BCMA levels in a dose-dependent fashion, concurrently decreased sBCMA concentrations, and improved tumor recognition by CAR T cells in vitro. GSI treatment of MM tumor-bearing NOD/SCID/gammac-/- mice increased BCMA expression on tumor cells, decreased sBCMA in peripheral blood, and improved antitumor efficacy of BCMA-targeted CAR T-cell therapy. Importantly, short-term GSI administration to MM patients markedly increases the percentage of BCMA+ tumor cells, and the levels of BCMA surface expression in vivo. Based on these data, a US Food and Drug Administration (FDA)-approved clinical trial has been initiated, combining GSI with concurrent BCMA CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT03502577