Evaluating targeted therapies in older patients with TP53-mutated AML.

Mutation of thetumor suppressor gene, TP53 (tumor protein 53), occurs in up to 15% of all patients with acute myeloid leukemia (AML) and is enriched within specific clinical subsets, most notably in older adults, and including secondary AML cases arising from preceding myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS), patients exposed to prior DNA-damaging, cytotoxic therapies. In all cases, these tumors have remained difficult to effectively treat with conventional therapeutic regimens. Newer approaches fortreatmentofTP53-mutated AML have shifted to interventions that maymodulateTP53 function, target downstream molecular vulnerabilities, target non-p53 dependent molecular pathways, and/or elicit immunogenic responses. This review will describe the basic biology of TP53, the clinical and biological patterns of TP53 within myeloid neoplasms with a focus on elderly AML patients and will summarize newer therapeutic strategies and current clinical trials.

A retrospective validation of the IPSS-M molecular score in primary and therapy-related myelodysplastic syndromes (MDS).

A molecular scoring system (IPSS-M) was recently proposed for myelodysplastic syndrome (MDS). We conducted a retrospective study of adults with MDS referred 2019-2021. The primary outcomes were leukemia-free survival (LFS) and overall survival (OS). One hundred and forty-four patients diagnosed between 2011 and 2021 were analyzed. After IPSS-M re-stratification, 33% of patients were up-staged and 11% down-staged. Median follow-up was 2.8 years and 53 patients died (37%). Cumulative incidence of acute myeloid leukemia (AML) transformation was 20% at 3 years post-diagnosis. International Prognostic Scoring System (IPSS), revised version (IPSS-R) was significantly associated with LFS (log-rank p = 9.2e-05; 'very high' vs. 'low' risk HR = 3.85, p = 5.8e-04) and OS (log-rank p = 7.2e-06; 'very high' vs. 'low' HR = 5.09, p = 1.7e-04). IPSS-M was also a significant predictor of LFS (log-rank p = 1.1e-06; 'very high' vs. 'low' HR = 4.97, p = 2.2e-05) and OS (log-rank p = 4.8e-07; 'very high' vs. 'low' HR = 6.42, p = 2.5e-05) while providing better discrimination than IPSS-R for both outcomes. This mutation-incorporating prognostic index has greater discriminative potential than IPSS-R to predict AML transformation and any-cause mortality.

Next-generation sequencing-based MRD in adults with ALL undergoing hematopoietic cell transplantation.

Measurable residual disease (MRD) is an adverse prognostic factor in adult patients with acute lymphoblastic leukemia (ALL) undergoing hematopoietic cell transplant (HCT). Next-generation sequencing (NGS) can detect MRD with a sensitivity of 10-6, but the prognostic value of NGS-based MRD in adult patients with ALL undergoing HCT remains minimally studied. To evaluate the prognostic value of NGS-based MRD in adult patients with ALL undergoing HCT, patients aged ≥18 years with ALL who underwent allogeneic HCT at Stanford University or Oregon Health & Science University between January 2014 and April 2021 and were evaluated for MRD using the NGS-based clonoSEQ assay were included in this study. MRD was assessed before HCT (MRDpre) and up to 1 year after HCT (MRDpost). Patients were followed up for leukemia relapse and survival for up to 2 years after HCT. In total, 158 patients had a trackable clonotype for MRD monitoring. The cumulative incidence of relapse was increased at all levels of MRDpre, including in patients who had low MRDpre of <10-4 (hazard ratio [HR], 3.56; 95% confidence interval [95% CI], 1.39-9.15). In multivariable analysis, MRDpre level remained significantly prognostic; however, detectable MRDpost was the strongest predictor of relapse (HR, 4.60; 95% CI, 3.01-7.02). In exploratory analyses limited to patients with B-cell ALL, the detection of post-HCT immunoglobulin H (IgH) MRD clonotypes, rather than non-IgH MRD clonotypes, was associated with relapse. In this analysis across 2 large transplant centers, we found that the detection of MRD by NGS at a level of 10-6 offers significant prognostic value in adults with ALL undergoing HCT.

Clinical predictors for thrombus progression in cirrhotic patients with untreated splanchnic vein thrombosis.

INTRODUCTION: Splanchnic vein thrombosis (SVT) occurs in a heterogenous group of patients secondary to a variety of risk factors including liver disease. Minimal data regarding natural history and outcomes of SVT exists to inform management decisions. As such, there is equipoise regarding the utility of anticoagulation in cirrhotic patients with SVT. We sought to identify clinical factors predictive of new or progressive thrombosis in a cohort of patients with untreated SVT. METHODS: We conducted a retrospective cohort study of cirrhotic patients over 18 years of age diagnosed with SVT at the Oregon Health & Science University from 2015 to 2020, excluding those initially treated with anticoagulation. The primary study endpoint was a composite of the following: imaging-confirmed progression of SVT, development of cavernous transformation, intestinal ischemia, portal cholangiopathy or new venous or arterial thrombosis. RESULTS: 261 patients were included in the analysis (median age 61 years, 68% male, 32% female). Forty percent of all patients experienced the primary composite endpoint. Multivariable logistic regression found that only the presence of pancreatitis or abdominal infection at diagnosis was associated with an increased likelihood of experiencing thrombus progression in patients with untreated SVT (OR 3.61, P = 0.02). There was a statistically significant overall survival difference between patients that did and did not experience the primary composite endpoint after controlling for confounding variables. (p = 0.0068). CONCLUSIONS: Overall, only the presence of pancreatitis or intrabdominal infection were found to be significantly associated with thrombotic progression, with varices identified as marginally non-significant risk factor. Notably, thrombotic progression was associated with a significant reduction in overall survival.

KLHL6 Is Preferentially Expressed in Germinal Center-Derived B-Cell Lymphomas.

OBJECTIVES: KLHL6 is a recently described BTB-Kelch protein with selective expression in lymphoid tissues and is most strongly expressed in germinal center B cells. METHODS: Using gene expression profiling as well as immunohistochemistry with an anti-KLHL6 monoclonal antibody, we have characterized the expression of this molecule in normal and neoplastic tissues. Protein expression was evaluated in 1,058 hematopoietic neoplasms. RESULTS: Consistent with its discovery as a germinal center marker, KLHL6 was positive mainly in B-cell neoplasms of germinal center derivation, including 95% of follicular lymphomas (106/112). B-cell lymphomas of non-germinal center derivation were generally negative (0/33 chronic lymphocytic leukemias/small lymphocytic lymphomas, 3/49 marginal zone lymphomas, and 2/66 mantle cell lymphomas). CONCLUSIONS: In addition to other germinal center markers, including BCL6, CD10, HGAL, and LMO2, KLHL6 immunohistochemistry may prove a useful adjunct in the diagnosis and future classification of B-cell lymphomas.

Clonal architecture of CXCR4 WHIM-like mutations in Waldenström Macroglobulinaemia.

CXCR4(WHIM) somatic mutations are distinctive to Waldenström Macroglobulinaemia (WM), and impact disease presentation and treatment outcome. The clonal architecture of CXCR4(WHIM) mutations remains to be delineated. We developed highly sensitive allele-specific polymerase chain reaction (AS-PCR) assays for detecting the most common CXCR4(WHIM) mutations (CXCR4(S338X C>A and C>G) ) in WM. The AS-PCR assays detected CXCR4(S338X) mutations in WM and IgM monoclonal gammopathy of unknown significance (MGUS) patients not revealed by Sanger sequencing. By combined AS-PCR and Sanger sequencing, CXCR4(WHIM) mutations were identified in 44/102 (43%), 21/62 (34%), 2/12 (17%) and 1/20 (5%) untreated WM, previously treated WM, IgM MGUS and marginal zone lymphoma patients, respectively, but no chronic lymphocytic leukaemia, multiple myeloma, non-IgM MGUS patients or healthy donors. Cancer cell fraction analysis in WM and IgM MGUS patients showed CXCR4(S338X) mutations were primarily subclonal, with highly variable clonal distribution (median 35·1%, range 1·2-97·5%). Combined AS-PCR and Sanger sequencing revealed multiple CXCR4(WHIM) mutations in many individual WM patients, including homozygous and compound heterozygous mutations validated by deep RNA sequencing. The findings show that CXCR4(WHIM) mutations are more common in WM than previously revealed, and are primarily subclonal, supporting their acquisition after MYD88(L265P) in WM oncogenesis. The presence of multiple CXCR4(WHIM) mutations within individual WM patients may be indicative of targeted CXCR4 genomic instability.