Zhang, Ben

Abstract In this study, we aimed to characterize the molecular mechanisms of two very rare subtypes of AML: acute megakaryoblastic leukemia (AMKL) and acute panmyelosis with myelofibrosis (APMF). Our goal is to describe the clinical-pathologic features of APMF and explore the genomic landscape AMKL to further understand these rare malignancies. We identified 35 patients diagnosed with AMKL (n=27) and APMF (n=8) at Mayo Clinic between 1995 and 2015 by retrospective chart review. For 10 of the AMKL patients, tissue was available for whole-exome sequencing and was analyzed in comparison to a published AML reference population. The median overall survival was shorter in patients with AMKL (3.9 months, 95% CI 1.7-7.4) than in patients with APMF (14.3 months, 95% CI 0.7-NE, p = 0.026,). For both AMKL and APMF, patients who underwent allogeneic hematopoietic stem cell transplantation had better overall survival (14.3 months, 95% CI 1.9-NE) compared to those not undergoing transplantation (4.6 months, 95% CI 1.5-7.4, p = 0.003). Patients with AMKL presented more frequently with splenomegaly, with higher peripheral blood blast counts, and with higher serum lactate dehydrogenase concentrations. 9 out of 10 AMKL patients with available tissue for sequencing demonstrated variants in 22 of 35 AML driver genes, with JAK2 V617F as the most common mutation. Although our small study numbers preclude firm conclusions, it does reflect the rarity of these AML subtypes. Furthermore, inferior survival in AMKL (compared to APMF) was reflected in its proliferative disease features such as splenomegaly, high blast counts, and high lactate dehydrogenase. Interestingly, the presence of JAK2 V617F variants in 40% of the interrogated samples was higher than expected. Although JAK2 is a known molecular driver in myeloproliferative neoplasms, it is actually very rare in de novo AML (~1%). Despite improved survival with allogeneic stem cell transplant, we can conclude that treatment outcomes for AMKL and APMF with standard-of-care therapy were sobering and that patients with these rare AML subtypes should undergo molecular evaluation to qualify them for clinical trials with novel targeted therapies. Citation Format: Marissa Li, Moritz Binder, Basma Basha, Ben Zhang, Alejandro Ferrer, Yuanhan Liu, Mrinal Patnaik, David Viswanatha, Naseema Gangat. Acute megakaryoblastic leukemia is associated with poor overall survival and enriched in JAK2 variants [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B03.

Abstract Introduction Acute panmyelosis with myelofibrosis (APMF) is classified under acute myeloid leukemia not otherwise specified by World Health organization (WHO). The clinical course of this entity is rapidly progressive and fatal, therefore, it is essential to make the accurate diagnosis and distinguish it from its mimickers, particularly acute megakaryoblastic leukemia; AML-M7 (AMKL). The main objective of this study is to identify clinical and pathologic features which could help distinguish APMF from AMKL. Methods We evaluated all patients treated at our institution between 1994 and 2013, with APMF and AMKL. We retrospectively reviewed their clinical data, laboratory results, and initial bone marrow morphologic evaluation. The lineage of blasts was evaluated using immunohistochemical staining with antibodies to CD34, anti-megakaryocyte antibodies CD41, CD61, and polyclonal factor VIII. Flow cytometry and cytogenetic studies were reviewed. Results i) Clinical characteristics 28 patients were studied which included 8 with APMF (median age 63 years) and 20 with AMKL (median age 65 years). Splenomegaly was commonly seen in AMKL (40%) as opposed to APMF (12.5%) (P=0.21). None of the APMF patients had an antecedent hematologic malignancy, compared to 50% of AMKL patients (p=0.02). Accordingly, APMF patients had a lower incidence of the JAK2V617F mutation compared to AMKL (14% vs. 78%, p=0.04). ii) Pathological features Patients with APMF had a hypercellular marrow with increased erythropoiesis (87% vs. 10%, p<0.01) and granulopoiesis (100% vs. 25%, p<0.01), with lower bone marrow blast percentage (14% vs. 33%, p<0.01), with all blasts staining positive for CD34 (p=0.23) compared with AMKL. In AMKL, the majority of blasts stain positive for anti-megakaryocytic antibodies CD61 (100% vs. 30%, p=0.02), CD41 (75% vs. 20%, p=0.10), and factor VIII (50% vs. 20%, p=0.02). On flow cytometry, all cases of APMF demonstrated multilineage proliferation with subsets of blasts positive for CD61, CD117, and MPO. In comparison, all cases of AMKL expressed megakaryocytic marker CD61. iii) Treatment Half of our patients received intensive induction chemotherapy in each group. Median survival was similar in APMF and AMKL of 8.6 and 7.6 months respectively (P=0.82). Of the 8 APMF patients, two are alive, with follow-up duration of 14 and 20 months, respectively. In the AMKL group, only one patient is alive, with follow-up duration of 55 months. All three patients have undergone allogeneic bone marrow transplant. Conclusion In summary, our study illustrated important clinical and pathologic differences between APMF and AMKL, two similar but distinct conditions. Allogenic stem cell transplant has shown promise in limited number of cases. Future trials evaluating the efficacy of novel therapies are warranted.Table 1Clinical and Laboratory features including treatment details of patients with APMF and AMKLAPMFN=8AMKLN=20P-valueAge in years (median)63650.11Gender, M:F5:310:100.69Splenomegaly at diagnosis, n (%)1 (12.5)8 (40)0.21Antecedent hematological malignancy08- myeloproliferative neoplasm 2- myelodysplastic syndromes0.02Hgb [median] g/dl9.68.70.73WBC [median] x 109/L1.14.40.15Platelets [median ] X 109/L28360.29Blast % [median]2130.47LDH [median]4227090.12JAK2V617F mutation, n (%)1/7 (14)7/9 (78)0.04Bone marrow Cellularity, n (%): - Hypercellular - Normocellular - Hypocellular8 (100) 13 (65) 4 (20) 3 (15)0.07 0.29 0.54↑erythropoiesis, n (%)7 (87)2 (10)<0.01Left shift, n (%)5 (62)6 (30)0.20↑granulopoiesis, n (%)8 (100)5 (25)<0.01Left shift, n (%)8 (100)9 (55)0.01↑megakaryopoiesis, n (%)7 (87)16 (80)1.00Micromegakaryocytes, n (%)7 (87)18 (90)1.00↓megakaryocyte nuclear lobulation, n(%)7 (87)12 (60)0.21Clustering of megakaryocytes, n (%)5 (62)13 (65)1.00BM blast % [median]3314<0.01% of blasts CD34 + [median]100300.23% of blasts + for megakaryocyte markers [median] - CD61+ - CD41+ - Factor VIII+30 20 20100 75 500.020.10 0.01Reticulin fibrosis ≥ 3+, n (%)5 (62)9 (45)0.67Complex karyotype, n (%)4(50)10(50)1.00Treatment, n (%) - Induction chemotherapy - Hypomethylating agent - Clinical trial - Supportive care4 (50) 0 0 4(50)10(50) 2(10) 2 (10) 6(30)Allogeneic bone marrow transplant, n (%)3 (38)3 (15)Overall survival in months (median)8.677.610.82 Disclosures No relevant conflicts of interest to declare.

Abstract Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

359 Background: Sarcomatoid renal cell carcinoma (RCC) is an aggressive form of RCC and is associated with a poor prognosis. Standard therapies tend to be less effective in this subset of patients. Methods: Using the Mayo Clinic Nephrectomy Registry, 206 patients with sarcomatoid RCC treated with partial or radical nephrectomy were identified. These patients were characterized based on extent of disease, treatment response and survival. Results: Of these 206, there was no evidence of distant metastases in 110 patients at the time of surgery and the estimated distant metastases-free survival at one year was 44%. The estimated cancer-specific survival rate at one and five years was 56% and 20%, respectively. Compared to patients with grade 4 RCC without sarcomatoid features, those with sarcomatoid RCC were more likely to develop distant metastases following surgery (hazard ratio 1.49). Considering those with metastatic sarcomatoid RCC, 96 patients had metastases at the time of surgery and 77 with no metastases at the time of surgery subsequently developed distant metastases (n=173). Of these, 156 died at a mean of 1.0 years from time of first evidence of distant metastases with a median cancer-specific survival of 0.6 years. Estimated cancer-specific survival rates from time of first metastases at one year and five years were 34% and 4%, respectively. The most common metastatic sites: lung (46%), bone (15%), liver (13%), non-regional lymph nodes (9%), and brain (5%). Patients who received targeted systemic therapy (10%) with either sunitinib (n=14), sorafenib (2) or pazopanib (1) for their first occurrence of distant metastases had an estimated cancer-specific survival rate at one year of 69%, compared to 30% for patients who did not. Median cancer-specific survival for those receiving targeted therapy as first-line was 2.2 years compared to 0.6 years for those patients who did not. Conclusions: Sarcomatoid RCC is an aggressive subtype of kidney cancer as evidenced by poor survival rates. The patients in this registry with metastatic sarcomatoid RCC who received targeted therapy as first-line treatment had improved cancer-specific survival rates.

Treatment with abiraterone acetate and prednisone (AA/P) prolongs survival in metastatic castration-resistant prostate cancer (mCRPC) patients. We evaluated the genetic variation in CYP17A1 as predictive of response to AA/P. A prospective collection of germline DNA prior to AA/P initiation and follow-up of a mCRPC cohort was performed. Five common single-nucleotide polymorphisms (SNPs) in CYP17A1 identified using a haplotype-based tagging algorithm were genotyped. Clinical outcomes included biochemical response and time to biochemical progression on AA/P. Logistic regression was used to assess the association between tag SNPs and biochemical response. Proportional hazards regression was used to assess the association between tag SNPs and time to biochemical progression. Odds or hazard ratio per minor allele were estimated and p-values below 0.05 were considered statistically significant. Germline DNA was successfully genotyped for four tag SNPs in 87 patients. The median age was 73 years (54–90); the median prostate-specific antigen was 66 ng/dL (0.1–99.9). A single SNP, rs2486758, was associated with lower odds of experiencing a biochemical response (Odds ratio 0.22, 95% confidence interval 0.07–0.63, p = 0.005) and a shorter time to biochemical progression (Hazard ratio 2.23, 95% confidence interval 1.39–3.56, p < 0.001). This tag SNP located in the promoter region of CYP17A1 will need further validation as a predictive biomarker for AA/P therapy.

Cardiac metastasis in renal cell carcinoma is a very rare entity, with only a few previously reported cases. In this series, we report two cases of ventricular metastases from renal cell carcinoma without vena cava or right atrial involvement. The first case involves an initially isolated inoperable metastasis to the left ventricle, which was treated with systemic targeted therapy with favorable local response. Our second case illustrates a patient with an isolated cardiac metastasis in the interventricular septum with extension into the right ventricle, which has also remained stable in size on systemic targeted therapy. Although anti-angiogenic agents such as tyrosine kinase inhibitors have transformed the treatment of metastatic renal cell carcinoma in recent years, their efficacy and safety in treating patients with metastatic disease in highly vascular organs such as the heart are currently unknown, with no prior reports on this topic. We describe our novel management of these unique cases and discuss the current medical and surgical approaches to treating cardiac metastases from renal cell carcinoma.