Cancer patients with clonal hematopoiesis die from primary malignancy or comorbidities despite higher rates of transformation to myeloid neoplasms.

BACKGROUND: The occurrence of somatic mutations in patients with no evidence of hematological disorders is called clonal hematopoiesis (CH). CH, whose subtypes include CH of indeterminate potential and clonal cytopenia of undetermined significance, has been associated with both hematologic cancers and systemic comorbidities. However, CH's effect on patients, especially those with concomitant malignancies, is not fully understood. METHODS: We performed a retrospective evaluation of all patients with CH at a tertiary cancer center. Patient characteristics, mutational data, and outcomes were collected and analyzed. RESULTS: Of 78 individuals included, 59 (76%) had a history of cancer and 60 (77%) had moderate to severe comorbidity burdens. DNMT3A, TET2, TP53, and ASXL1 were the most common mutations. For the entire cohort, the 2-year overall survival rate was 79% (95% CI: 70, 90), while the median survival was not reached. Of 20 observed deaths, most were related to primary malignancies (n = 7, 35%), comorbidities (n = 4, 20%), or myeloid neoplasms (n = 4, 20%). Twelve patients (15%) experienced transformation to a myeloid neoplasm. According to the clonal hematopoiesis risk score, the 3-year transformation rate was 0% in low-risk, 15% in intermediate-risk (p = 0.098), and 28% in high-risk (p = 0.05) patients. By multivariate analysis, transformation was associated with variant allele frequency ≥0.2 and hemoglobin <10 g/dL. CONCLUSIONS: In a population including mostly cancer patients, CH was associated with comorbidities and myeloid transformation in patients with higher mutational burdens and anemia. Nevertheless, such patients were less likely to die of their myeloid neoplasm than of primary malignancy or comorbidities.

Current Understanding of DDX41 Mutations in Myeloid Neoplasms.

The DEAD-box RNA helicase 41 gene, DDX41, is frequently mutated in hereditary myeloid neoplasms, identified in 2% of entire patients with AML/MDS. The pathogenesis of DDX41 mutation is related to the defect in the gene's normal functions of RNA and innate immunity. About 80% of patients with germline DDX41 mutations have somatic mutations in another allele, resulting in the biallelic DDX41 mutation. Patients with the disease with DDX41 mutations reportedly often present with the higher-grade disease, but there are conflicting reports about its impact on survival outcomes. Recent studies using larger cohorts reported a favorable outcome with a better response to standard therapies in patients with DDX41 mutations to patients without DDX41 mutations. For stem-cell transplantation, it is important for patients with DDX41 germline mutations to identify family donors early to improve outcomes. Still, there is a gap in knowledge on whether germline DDX41 mutations and its pathology features can be targetable for treatment, and what constitutes an appropriate screening/surveillance strategy for identified carriers. This article reviews our current understanding of DDX41 mutations in myeloid neoplasms in pathologic and clinical features and their clinical implications.

Implications of RAS mutational status in subsets of patients with newly diagnosed acute myeloid leukemia across therapy subtypes.

Activating mutations in RAS have been reported in about 10-15% of patients with AML; previous studies have not identified a prognostic significance. However, RAS mutations have emerged as a potential resistance mechanism to treatment with inhibitors of FLT3, IDH, and BCL2. We aimed to determine the characteristics and outcomes of patients with RAS-mutated (RAS-mut) AML across therapy subsets of 1410 patients newly diagnosed (ND AML). RAS-mut was observed in 273 (20%) patients. Overall, patients with RAS-mut AML had an estimated 3-year survival rate of 38% vs. 28% in those with RAS wild type (RAS-wt), p = .01. Among patients with RAS-mut, favorable karyotype and concomitant NPM1 mutations were associated with a higher CR/CRi rate, OR 23.2 (95% CI: 2.7-192.7; p < .001) and OR 2.8 (95% CI: 1.1-6.9; p = .02), respectively, while secondary and treated secondary (ts)-AML were associated with low response rates, OR 0.34 (95% CI: 0.1-0.9; p = .04) and OR 0.22 (95% CI: 0.09-0.5; p = .001), respectively. Intensive chemotherapy was associated with high response rates OR 5.9 (95% CI: 2.9-12.2; p < .001). Better median OS was observed among those with favorable karyotype, HR 0.28 (95% CI: 0.1-0.6; p = .002), and those treated with intensive chemotherapy, HR 0.42 (95% CI: 0.2-0.6 p < .001). Conversely, ts- AML and co-occurrence of mutations in TP53 were associated with poor median OS; HR 2.3 (95% CI: 1.4-3.9; p = .001) and HR 1.7 (95% CI: 0.9-3.1; p = .06), respectively. The addition of venetoclax was associated with a non-significant improvement in CR/CRi and OS.

Venetoclax resistance: mechanistic insights and future strategies.

Acute myeloid leukemia (AML) is historically associated with poor prognosis, especially in older AML patients unfit for intensive chemotherapy. The development of Venetoclax, a potent oral BH3 (BCL-2 homology domain 3) mimetic, has transformed the AML treatment. However, the short duration of response and development of resistance remain major concerns. Understanding mechanisms of resistance is pivotal to devising new strategies and designing rational drug combination regimens. In this review, we will provide a comprehensive summary of the known mechanisms of resistance to Venetoclax and discuss Venetoclax-based combination therapies. Key contributing factors to Venetoclax resistance include dependencies on alternative anti-apoptotic BCL-2 family proteins and selection of the activating kinase mutations. Mutational landscape governing response to Venetoclax and strategic approaches developed considering current knowledge of mechanisms of resistance will be addressed.

Urgent cytoreduction for newly diagnosed acute myeloid leukemia patients allows acquisition of pretreatment genomic data and enrollment on investigational clinical trials.

Newly diagnosed acute myeloid leukemia is often deemed a medical emergency, requiring urgent treatment. This is in contradiction with the need for accurate cytogenetic and molecular data, which is not immediately available, to select optimal therapy. We hypothesized that cytoreduction with hydroxyurea or cytarabine would enable urgent disease control and provide a bridge to clinical trial enrollment. We analyzed three prospective frontline clinical trials that allowed the use of cytoreduction before treatment initiation. Among 274 patients with a median age of 62 (range, 18-89), there was no significant difference in short- and long-term outcome and safety among patients who did (CytoRed) or did not receive (NoCytoRed) cytoreduction. The overall response rate in CytoRed group was 91%, compared with 86% in NoCytoRed group (p = .264). The 30- and 60-day mortality rates were 2% and 7% in CytoRed group, compared with 2% (p = .978) and 6% (p = .652) in NoCytoRed group, respectively. There was no significant difference in overall survival (OS) between in CytoRed group compared with NoCytoRed group (Hazard ratio 0.97, 95% CI 0.70-1.37, p = .879). Results were unchanged after stratification by age (< or ≥65 years) or after multivariate analyses for OS. Our data suggests that urgent cytoreduction using hydroxyurea or cytarabine is a feasible and safe approach to facilitate acquisition of complete diagnostic information prior to treatment initiation on a clinical trial.

A randomized phase 2 trial of idiotype vaccination and adoptive autologous T-cell transfer in patients with multiple myeloma.

We hypothesized that combining adoptively transferred autologous T cells with a cancer vaccine strategy would enhance therapeutic efficacy by adding antimyeloma idiotype (Id)-keyhole limpet hemocyanin (KLH) vaccine to vaccine-specific costimulated T cells. In this randomized phase 2 trial, patients received either control (KLH only) or Id-KLH vaccine, autologous transplantation, vaccine-specific costimulated T cells expanded ex vivo, and 2 booster doses of assigned vaccine. In 36 patients (KLH, n = 20; Id-KLH, n = 16), no dose-limiting toxicity was seen. At last evaluation, 6 (30%) and 8 patients (50%) had achieved complete remission in KLH-only and Id-KLH arms, respectively (P = .22), and no difference in 3-year progression-free survival was observed (59% and 56%, respectively; P = .32). In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with patients receiving KLH only, there was a greater change in IR genes in T cells in those receiving Id-KLH relative to baseline. Specifically, upregulation of genes associated with activation, effector function induction, and memory CD8+ T-cell generation after Id-KLH but not after KLH control vaccination was observed. Similarly, in responding patients across both arms, upregulation of genes associated with T-cell activation was seen. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of patients receiving Id-KLH. In conclusion, in this combination immunotherapy approach, we observed significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm, supporting further investigation of vaccine and adoptive immunotherapy strategies. This trial was registered at www.clinicaltrials.gov as #NCT01426828.

Phase II study of azacitidine with pembrolizumab in patients with intermediate-1 or higher-risk myelodysplastic syndrome.

Programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) expression is upregulated in cluster of differentiation 34 (CD34)+ bone marrow cells from patients with myelodysplastic syndromes (MDS). Hypomethylating agent (HMA) treatment results in further increased expression of these immune checkpoints. We hypothesised that combining an anti-PD-1 antibody with HMAs may have efficacy in patients with MDS. To test this concept, we designed a phase II trial of the combination of azacitidine and pembrolizumab with two cohorts. In the 17 previously untreated patients, the overall response rate (ORR) was 76%, with a complete response (CR) rate of 18% and median overall survival (mOS) not reached after a median follow-up of 12·8 months. For the HMA-failure cohort (n = 20), the ORR was 25% and CR rate was 5%; with a median follow-up of 6·0 months, the mOS was 5·8 months. The most observed toxicities were pneumonia (32%), arthralgias (24%) and constipation (24%). Immune-related adverse events requiring corticosteroids were required in 43%. Overall, this phase II trial suggests that azacitidine and pembrolizumab is safe with manageable toxicities in patients with higher-risk MDS. This combined therapy may have anti-tumour activity in a subset of patients and merits further studies in the front-line setting.

Outcomes of TP53-mutant acute myeloid leukemia with decitabine and venetoclax.

BACKGROUND: TP53 mutation (TP53mut ) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients; however, recent reports suggest that TP53mut confers resistance to venetoclax. The authors investigated the outcomes of patients with TP53mut AML who were treated with a 10-day decitabine and venetoclax (DEC10-VEN) (ClinicalTrials.gov identifier NCT03404193). METHODS: Patients with newly diagnosed AML received decitabine 20 mg/m2 for 10 days every 4 to 6 weeks for induction, followed by decitabine for 5 days after response. The venetoclax dose was 400 mg daily. TP53mut was identified in bone marrow samples using next-generation sequencing, with sensitivity of 5%. Outcomes were analyzed according to European LeukemiaNet 2017 guidelines. RESULTS: Among 118 patients (median age, 72 years; age range, 49-89 years), 63 (53%) had secondary AML, 39 (33%) had AML with complex karyotype, and 35 (30%) had TP53mut AML. The median TP53 variant allele frequency was 32% (interquartile range, 16%-65%), 8 patients (23%) had only a single TP53 mutation, 15 (43%) had multiple mutations, and 12 (34%) had mutation and deletion. Outcomes were significantly worse in patients who had TP53mut AML compared with those who had wild-type TP53 AML, with an overall response rate of 66% vs 89% (P = .002), a complete response/complete response with incomplete hematologic recovery rate of 57% vs 77% (P = .029), and a 60-day mortality of 26% vs 4% (P < .001), respectively. Patients with TP53mut versus wild-type TP53 had shorter overall survival at 5.2 versus 19.4 months, respectively (hazard ratio, 4.67; 95% CI, 2.44-8.93; P < .0001), and shorter relapse-free survival at 3.4 versus 18.9 months (hazard ratio, 4.80; 95% CI, 1.97-11.69; P < .0001), respectively. Outcomes with DEC10-VEN in patients with TP53mut AML were comparable to historical results with 10-day decitabine alone. CONCLUSIONS: Patients with TP53mut AML have lower response rates and shorter survival with DEC10-VEN.

Current Approaches to Philadelphia Chromosome-Positive B-Cell Lineage Acute Lymphoblastic Leukemia: Role of Tyrosine Kinase Inhibitor and Stem Cell Transplant.

PURPOSE OF REVIEW: Over the past two decades, tyrosine kinase inhibitors (TKIs) have changed the management of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), and this has led to significant improvement in their outcome. In this review, we will provide an overview of the current understanding of treatment of Ph+ ALL focusing on TKIs, alloHSCT, and novel therapies. RECENT FINDINGS: The advent of more potent TKIs and the novel therapeutic options including blinatumomab, inotuzumab ozogamicin, and CD19 CAR-T therapy has changed the role of allogeneic hematopoietic stem cell transplant (alloHSCT) and intensive chemotherapy. To avoid toxicity from the historical treatment strategies, a more individualized, targeted approach to therapy including detection and monitoring of measurable residual disease (MRD) has become of interest. The treatment of patients with Ph+ ALL has been rapidly evolving with a more individualized, targeted treatment and use of TKIs and novel therapy.

The use of direct acting oral anticoagulants in patients with COVID-19 infection.

The use of direct-acting oral anticoagulants (DOACs) has increased rapidly in the last decade; becoming the mainstay for both the prophylaxis and the treatment of venous thromboembolism in various situations including non-valvular atrial fibrillation, joint replacement surgeries and acute DVT/PE, etc. In the present times, DOACs are possibly one of the most widely prescribed medications in the developed world. The worldwide epidemic caused by COVID-19 caused significant changes in the practice of medicine worldwide. Patients who developed severe respiratory illness caused by COVID-19 were noted to develop a wide range of complications, including both arterial and venous thromboembolic complications including deep vein thrombosis and pulmonary embolism, etc. This review is an attempt to identify the role of DOACs in the treatment and prevention of these complications as well as the safety of continuing therapy with DOACs in the patients who were receiving them before contracting the infection.

Incidental early diagnosis of biphasic pulmonary blastoma in a patient with history of stage IV lung adenocarcinoma.

Biphasic pulmonary blastoma is a rare but lethal type of lung malignancy with characteristic histology of both epithelial and mesenchymal components. Previously reported cases have been limited to presentation at advanced stages, suggesting that the clinical course of the disease is usually aggressive. Here, we report a case of incidental diagnosis of biphasic pulmonary blastoma by imaging surveillance in a patient previously treated for adenocarcinoma of the lung. The patient was diagnosed with stage 1 disease and underwent successful resection. Next-generation sequencing (NGS) revealed a high mutation burden, a finding not previously reported in a patient with biphasic pulmonary blastoma.

An Unusual Initial Presentation of Diffuse Large B-Cell Lymphoma as Recurrent Syncope.

We describe a rare presentation of diffuse large B-cell Lymphoma (DLBCL) with recurrent episodes of syncope. During the workup for syncope, the patient was incidentally found to have an extensive mass in the left thorax, which was later diagnosed as stage 2 bulky disease DLBCL. This is the rare case of lymphoma presenting as recurrent syncope without cardiac involvement. The patient did not have any further episodes of syncope after her successful treatment of DLBCL.

Association between melanoma and renal-cell carcinoma for sequential diagnoses: A single-center retrospective study.

BACKGROUND: Melanoma and renal-cell carcinoma (RCC) are known to be immunological neoplasms. Previous studies have shown increased risks in patients with melanoma of developing RCC and in those with RCC of developing melanoma. However, data regarding immunocompromised status in these patients are lacking. METHODS: We conducted a retrospective review of patients who had a diagnosis of melanoma and/or RCC. Using summary statistics, we calculated total person-years at risk for developing melanoma among patients with RCC and for developing RCC among patients with melanoma, and compared the results with the SEER data. We also assessed medical history related to immune status and the use of immunosuppressive drugs. RESULTS: Among 13,879 patients with melanoma and 7597 patients with RCC, 89 had diagnoses of both melanoma and RCC (0.6% and 1.2% of melanoma and RCC patients, respectively): eight were diagnosed with both cancers concurrently, 54 were diagnosed with melanoma first, and 27 were diagnosed with RCC first. Standardized incidence ratios (SIRs) were 2.87 (95%CI 2.16-3.74) for developing RCC among the melanoma patients and 2.31 (95%CI 1.52-3.37) for developing melanoma among the RCC patients, compared to age-, sex-, race-, and calendar-specific adjusted incidence rates of each cancer in the SEER registry. None of the 81 patients with sequential diagnoses had a history of immunocompromised disease, nor did they receive chronic immunosuppressive drugs. Only two received chemotherapy and/or radiotherapy. CONCLUSION: We demonstrated a strong association between the diagnoses of melanoma and RCC. These increased risks could not be attributed to either immune status or previous antineoplastic treatment.

Comprehensive Evaluation of Programmed Death-Ligand 1 Expression in Primary and Metastatic Prostate Cancer.

Antibodies targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-L1) interaction have shown clinical activity in multiple cancer types. PD-L1 protein expression is a clinically validated predictive biomarker of response for such therapies. Prior studies evaluating the expression of PD-L1 in primary prostate cancers have reported highly variable rates of PD-L1 positivity. In addition, limited data exist on PD-L1 expression in metastatic castrate-resistant prostate cancer (mCRPC). Here, we determined PD-L1 protein expression by immunohistochemistry using a validated PD-L1-specific antibody (SP263) in a large and representative cohort of primary prostate cancers and prostate cancer metastases. The study included 539 primary prostate cancers comprising 508 acinar adenocarcinomas, 24 prostatic duct adenocarcinomas, 7 small-cell carcinomas, and a total of 57 cases of mCRPC. PD-L1 positivity was low in primary acinar adenocarcinoma, with only 7.7% of cases showing detectable PD-L1 staining. Increased levels of PD-L1 expression were noted in 42.9% of small-cell carcinomas. In mCRPC, 31.6% of cases showed PD-L1-specific immunoreactivity. In conclusion, in this comprehensive evaluation of PD-L1 expression in prostate cancer, PD-L1 expression is rare in primary prostate cancers, but increased rates of PD-L1 positivity were observed in mCRPC. These results will be important for the future clinical development of programmed cell death protein 1/PD-L1-targeting therapies in prostate cancer.

Novel BAFF-Receptor Antibody to Natively Folded Recombinant Protein Eliminates Drug-Resistant Human B-cell Malignancies In Vivo.

Purpose: mAbs such as anti-CD20 rituximab are proven therapies in B-cell malignancies, yet many patients develop resistance. Novel therapies against alternative targets are needed to circumvent resistance mechanisms. We sought to generate mAbs against human B-cell-activating factor receptor (BAFF-R/TNFRSF13C), which has not yet been targeted successfully for cancer therapy.Experimental Design: Novel mAbs were generated against BAFF-R, expressed as a natively folded cell surface immunogen on mouse fibroblast cells. Chimeric BAFF-R mAbs were developed and assessed for in vitro and in vivo monotherapy cytotoxicity. The chimeric mAbs were tested against human B-cell tumor lines, primary patient samples, and drug-resistant tumors.Results: Chimeric antibodies bound with high affinity to multiple human malignant B-cell lines and induced potent antibody-dependent cellular cytotoxicity (ADCC) against multiple subtypes of human lymphoma and leukemia, including primary tumors from patients who had relapsed after anti-CD20 therapy. Chimeric antibodies also induced ADCC against ibrutinib-resistant and rituximab-insensitive CD20-deficient variant lymphomas, respectively. Importantly, they demonstrated remarkable in vivo growth inhibition of drug-resistant tumor models in immunodeficient mice.Conclusions: Our method generated novel anti-BAFF-R antibody therapeutics with remarkable single-agent antitumor effects. We propose that these antibodies represent an effective new strategy for targeting and treating drug-resistant B-cell malignancies and warrant further development. Clin Cancer Res; 24(5); 1114-23. ©2017 AACR.

Understanding Hearing Loss and Barriers to Hearing Health Care Among Korean American Older Adults: A Focus Group Study.

Hearing loss is associated with an accelerated decline in social, cognitive, and physical functioning among older adults. However, little is known about its impact and barriers to hearing health care in any ethnic minorities. The aim of this study was to explore experiences related to hearing loss and barriers to hearing health care among older Korean Americans (KAs). We conducted four focus groups with 19 older KAs with hearing loss and four communication partners. Qualitative content analysis revealed four themes: (a) impact of hearing loss, (b) self-perception of hearing loss, (c) coping strategies for hearing loss, and (d) barriers to hearing health care (price, language, lack of collaborative communications, perceptions about hearing aids, and lack of knowledge). Older KAs were significantly impacted by hearing loss but tended not to seek care due to multiple factors. Culturally tailored hearing interventions are urgently needed to promote hearing health in the KA community.

AIM1 is an actin-binding protein that suppresses cell migration and micrometastatic dissemination.

A defining hallmark of primary and metastatic cancers is the migration and invasion of malignant cells. These invasive properties involve altered dynamics of the cytoskeleton and one of its major structural components ß-actin. Here we identify AIM1 (absent in melanoma 1) as an actin-binding protein that suppresses pro-invasive properties in benign prostate epithelium. Depletion of AIM1 in prostate epithelial cells increases cytoskeletal remodeling, intracellular traction forces, cell migration and invasion, and anchorage-independent growth. In addition, decreased AIM1 expression results in increased metastatic dissemination in vivo. AIM1 strongly associates with the actin cytoskeleton in prostate epithelial cells in normal tissues, but not in prostate cancers. In addition to a mislocalization of AIM1 from the actin cytoskeleton in invasive cancers, advanced prostate cancers often harbor AIM1 deletion and reduced expression. These findings implicate AIM1 as a key suppressor of invasive phenotypes that becomes dysregulated in primary and metastatic prostate cancer.

Nonstereotyped lymphoma B cell receptors recognize vimentin as a shared autoantigen.

Ag activation of the BCR may play a role in the pathogenesis of human follicular lymphoma (FL) and other B cell malignancies. However, the nature of the Ag(s) recognized by tumor BCRs has not been well studied. In this study, we used unbiased approaches to demonstrate that 42 (19.35%) of 217 tested FL Igs recognized vimentin as a shared autoantigen. The epitope was localized to the N-terminal region of vimentin for all vimentin-reactive tumor Igs. We confirmed specific binding to vimentin by using recombinant vimentin and by performing competitive inhibition studies. Furthermore, using indirect immunofluorescence staining, we showed that the vimentin-reactive tumor Igs colocalized with an anti-vimentin mAb in HEp-2 cells. The reactivity to N-terminal vimentin of IgG FL Igs was significantly higher than that of IgM FL Igs (30.4 versus 10%; p = 0.0022). However, vimentin-reactive FL Igs did not share CDR3 motifs and were not homologous. Vimentin was expressed in the T cell-rich regions of FL, suggesting that vimentin is available for binding with tumor BCRs within the tumor microenvironment. Vimentin was also frequently recognized by mantle cell lymphoma and multiple myeloma Igs. Our results demonstrate that vimentin is a shared autoantigen recognized by nonstereotyped FL BCRs and by the Igs of mantle cell lymphoma and multiple myeloma and suggest that vimentin may play a role in the pathogenesis of multiple B cell malignancies. These findings may lead to a better understanding of the biology and natural history of FL and other B cell malignancies.